Category Archives: Genetic medicine

Have you heard? A revolution has seized the scientific community. Within only a few years, research labs worldwide have adopted a new technology that facilitates making specific changes in the DNA of humans, other animals, and plants. Compared to previous techniques for modifying DNA, this new approach is much faster and easier. This technology is referred to as CRISPR, and it has changed not only the way basic research is conducted, but also the way we can now think about treating diseases [1,2].

CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeat. This name refers to the unique organization of short, partially palindromic repeated DNA sequences found in the genomes of bacteria and other microorganisms. While seemingly innocuous, CRISPR sequences are a crucial component of the immune systems [3] of these simple life forms. The immune system is responsible for protecting an organisms health and well-being. Just like us, bacterial cells can be invaded by viruses, which are small, infectious agents. If a viral infection threatens a bacterial cell, the CRISPR immune system can thwart the attack by destroying the genome of the invading virus [4]. The genome of the virus includes genetic material that is necessary for the virus to continue replicating. Thus, by destroying the viral genome, the CRISPR immune system protects bacteria from ongoing viral infection.

Figure 1 ~ The steps of CRISPR-mediated immunity. CRISPRs are regions in the bacterial genome that help defend against invading viruses. These regions are composed of short DNA repeats (black diamonds) and spacers (colored boxes). When a previously unseen virus infects a bacterium, a new spacer derived from the virus is incorporated amongst existing spacers. The CRISPR sequence is transcribed and processed to generate short CRISPR RNA molecules. The CRISPR RNA associates with and guides bacterial molecular machinery to a matching target sequence in the invading virus. The molecular machinery cuts up and destroys the invading viral genome. Figure adapted from Molecular Cell 54, April 24, 2014 [5].

Interspersed between the short DNA repeats of bacterial CRISPRs are similarly short variable sequences called spacers (FIGURE 1). These spacers are derived from DNA of viruses that have previously attacked the host bacterium [3]. Hence, spacers serve as a genetic memory of previous infections. If another infection by the same virus should occur, the CRISPR defense system will cut up any viral DNA sequence matching the spacer sequence and thus protect the bacterium from viral attack. If a previously unseen virus attacks, a new spacer is made and added to the chain of spacers and repeats.

The CRISPR immune system works to protect bacteria from repeated viral attack via three basic steps [5]:

Step 1) Adaptation DNA from an invading virus is processed into short segments that are inserted into the CRISPR sequence as new spacers.

Step 2) Production of CRISPR RNA CRISPR repeats and spacers in the bacterial DNA undergo transcription, the process of copying DNA into RNA (ribonucleic acid). Unlike the double-chain helix structure of DNA, the resulting RNA is a single-chain molecule. This RNA chain is cut into short pieces called CRISPR RNAs.

Step 3) Targeting CRISPR RNAs guide bacterial molecular machinery to destroy the viral material. Because CRISPR RNA sequences are copied from the viral DNA sequences acquired during adaptation, they are exact matches to the viral genome and thus serve as excellent guides.

The specificity of CRISPR-based immunity in recognizing and destroying invading viruses is not just useful for bacteria. Creative applications of this primitive yet elegant defense system have emerged in disciplines as diverse as industry, basic research, and medicine.

In Industry

The inherent functions of the CRISPR system are advantageous for industrial processes that utilize bacterial cultures. CRISPR-based immunity can be employed to make these cultures more resistant to viral attack, which would otherwise impede productivity. In fact, the original discovery of CRISPR immunity came from researchers at Danisco, a company in the food production industry [2,3]. Danisco scientists were studying a bacterium called Streptococcus thermophilus, which is used to make yogurts and cheeses. Certain viruses can infect this bacterium and damage the quality or quantity of the food. It was discovered that CRISPR sequences equipped S. thermophilus with immunity against such viral attack. Expanding beyond S. thermophilus to other useful bacteria, manufacturers can apply the same principles to improve culture sustainability and lifespan.

In the Lab

Beyond applications encompassing bacterial immune defenses, scientists have learned how to harness CRISPR technology in the lab [6] to make precise changes in the genes of organisms as diverse as fruit flies, fish, mice, plants and even human cells. Genes are defined by their specific sequences, which provide instructions on how to build and maintain an organisms cells. A change in the sequence of even one gene can significantly affect the biology of the cell and in turn may affect the health of an organism. CRISPR techniques allow scientists to modify specific genes while sparing all others, thus clarifying the association between a given gene and its consequence to the organism.

Rather than relying on bacteria to generate CRISPR RNAs, scientists first design and synthesize short RNA molecules that match a specific DNA sequencefor example, in a human cell. Then, like in the targeting step of the bacterial system, this guide RNA shuttles molecular machinery to the intended DNA target. Once localized to the DNA region of interest, the molecular machinery can silence a gene or even change the sequence of a gene (Figure 2)! This type of gene editing can be likened to editing a sentence with a word processor to delete words or correct spelling mistakes. One important application of such technology is to facilitate making animal models with precise genetic changes to study the progress and treatment of human diseases.

Figure 2 ~ Gene silencing and editing with CRISPR. Guide RNA designed to match the DNA region of interest directs molecular machinery to cut both strands of the targeted DNA. During gene silencing, the cell attempts to repair the broken DNA, but often does so with errors that disrupt the geneeffectively silencing it. For gene editing, a repair template with a specified change in sequence is added to the cell and incorporated into the DNA during the repair process. The targeted DNA is now altered to carry this new sequence.

In Medicine

With early successes in the lab, many are looking toward medical applications of CRISPR technology. One application is for the treatment of genetic diseases. The first evidence that CRISPR can be used to correct a mutant gene and reverse disease symptoms in a living animal was published earlier this year [7]. By replacing the mutant form of a gene with its correct sequence in adult mice, researchers demonstrated a cure for a rare liver disorder that could be achieved with a single treatment. In addition to treating heritable diseases, CRISPR can be used in the realm of infectious diseases, possibly providing a way to make more specific antibiotics that target only disease-causing bacterial strains while sparing beneficial bacteria [8]. A recent SITN Waves article discusses how this technique was also used to make white blood cells resistant to HIV infection [9].

Of course, any new technology takes some time to understand and perfect. It will be important to verify that a particular guide RNA is specific for its target gene, so that the CRISPR system does not mistakenly attack other genes. It will also be important to find a way to deliver CRISPR therapies into the body before they can become widely used in medicine. Although a lot remains to be discovered, there is no doubt that CRISPR has become a valuable tool in research. In fact, there is enough excitement in the field to warrant the launch of several Biotech start-ups that hope to use CRISPR-inspired technology to treat human diseases [8].

Ekaterina Pak is a Ph.D. student in the Biological and Biomedical Sciences program at Harvard Medical School.

1. Palca, J. A CRISPR way to fix faulty genes. (26 June 2014) NPR < http://www.npr.org/blogs/health/2014/06/26/325213397/a-crispr-way-to-fix-faulty-genes> [29 June 2014]

2. Pennisi, E. The CRISPR Craze. (2013) Science, 341 (6148): 833-836.

3. Barrangou, R., Fremaux, C., Deveau, H., Richards, M., Boyaval, P., Moineau, S., Romero, D.A., and Horvath, P. (2007). CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 17091712.

4. Brouns, S.J., Jore, M.M., Lundgren, M., Westra, E.R., Slijkhuis, R.J., Snijders, A.P., Dickman, M.J., Makarova, K.S., Koonin, E.V., and van der Oost, J. (2008). Small CRISPR RNAs guide antiviral defense in prokaryotes. Science 321, 960964.

5. Barrangou, R. and Marraffini, L. CRISPR-Cas Systems: Prokaryotes Upgrade to Adaptive Immunity (2014). Molecular Cell 54, 234-244.

6. Jinkek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. (2012) 337(6096):816-21.

7. CRISPR reverses disease symptoms in living animals for first time. (31 March 2014). Genetic Engineering and Biotechnology News. <http://www.genengnews.com/gen-news-highlights/crispr-reverses-disease-symptoms-in-living-animals-for-first-time/81249682/> [27 July 2014]

8. Pollack, A. A powerful new way to edit DNA. (3 March 2014). NYTimes < http://www.nytimes.com/2014/03/04/health/a-powerful-new-way-to-edit-dna.html?_r=0> [16 July 2014]

9. Gene editing technique allows for HIV resistance? <http://sitn.hms.harvard.edu/flash/waves/2014/gene-editing-technique-allows-for-hiv-resistance/> [13 June 2014]

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CRISPR: A game-changing genetic engineering technique

Taught by the genetic counselor faculty of the University of South Carolina Genetic Counseling Program, this specially designed genetic counseling online course,Genetic Counseling: Career for the Future, is comprised of lectures from genetic counselors, readings from professional literature and practical activities to help broaden your understanding of the profession and prepare for graduate school.

Online course topics include genetic counseling as a health care profession,with an introduction to various arenas of genetic counseling including prenatal, pediatric, cancer and adult. You'll explore clinical, laboratory and research roles, the counselor-patient relationship, ethical issues and other hot topics, as well as strategies for preparing for graduate education.

Fall: Sept. 12 - Nov. 18, 2022Register by Aug. 29

Winter: Jan. 9 - Mar. 17, 2023Register by Dec. 20

Summer: June 5 - Aug. 11, 2023Register by May 22

Register Now!

Questions can be directed to Genetics@uscmed.sc.edu

Our genetic counseling online course is offered over a 10-week period with two to three hours of self-paced activity per week. Upon completion, youll receive a continuing education certificate to add to your resume. There are no prerequisites for the course. Designed as an in-depth exploration of genetic counseling, the course will demonstrate your commitment to genetic counselor education at the same time you become savvy about the profession and considerations for graduate school.

The Genetic Counseling Program strives to increase diversity among genetic counselors and promotes an inclusive learning environment. As part of our Diversity Recruitment Initiative, a limited number of discounted registration fees will be granted to individuals of underrepresented communities of color. Come learn with us!

One of my reasons for taking this course was to feel inspired every week and gain further insight into the field of genetic counseling as I prepare for applications, and that is definitely happening! I really appreciate the range of assignments and I think it's a good combination to help structure our learning.

The work load is just right. Everything we have done has made me more and more excited about working towards my career as a genetic counselor.

I can tell that you have put a lot of time and effort into making this course as informative, up-to-date, and engaging as an in-person class.

It's fun to communicate with so many people with different backgrounds. Everyone shares their different experiences and I am constantly learning.

I've enjoyed reading the articles and responding to others on the discussion board. The videos have been so insightful --hearing from genetic counselors, learning about their jobs, and what excites them has been very meaningful to me.

With all of the information being online, I can start and stop the work as I please and always find time to do the readings and activities for the week. I really enjoy that the fact that the information comes from such a variety of resources...especially resources that I would have never known about otherwise. All of the articles, websites and videos have been so informative and learning more information about the field has deepened my passion for genetic counseling!"

You may also be interested in theSummer Internship.

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Genetic Counseling Online Course - School of Medicine Columbia ...

Bookshelf

A collection of biomedical books that can be searched directly or from linked data in other NCBI databases. The collection includes biomedical textbooks, other scientific titles, genetic resources such as GeneReviews, and NCBI help manuals.

A resource to provide a public, tracked record of reported relationships between human variation and observed health status with supporting evidence. Related information intheNIH Genetic Testing Registry (GTR),MedGen,Gene,OMIM,PubMedand other sources is accessible through hyperlinks on the records.

A registry and results database of publicly- and privately-supported clinical studies of human participants conducted around the world.

An archive and distribution center for the description and results of studies which investigate the interaction of genotype and phenotype. These studies include genome-wide association (GWAS), medical resequencing, molecular diagnostic assays, as well as association between genotype and non-clinical traits.

A searchable database of genes, focusing on genomes that have been completely sequenced and that have an active research community to contribute gene-specific data. Information includes nomenclature, chromosomal localization, gene products and their attributes (e.g., protein interactions), associated markers, phenotypes, interactions, and links to citations, sequences, variation details, maps, expression reports, homologs, protein domain content, and external databases.

A collection of expert-authored, peer-reviewed disease descriptions on the NCBI Bookshelf that apply genetic testing to the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions.

Summaries of information for selected genetic disorders with discussions of the underlying mutation(s) and clinical features, as well as links to related databases and organizations.

A voluntary registry of genetic tests and laboratories, with detailed information about the tests such as what is measured and analytic and clinical validity. GTR also is a nexus for information about genetic conditions and provides context-specific links to a variety of resources, including practice guidelines, published literature, and genetic data/information. The initial scope of GTR includes single gene tests for Mendelian disorders, as well as arrays, panels and pharmacogenetic tests.

A database of known interactions of HIV-1 proteins with proteins from human hosts. It provides annotated bibliographies of published reports of protein interactions, with links to the corresponding PubMed records and sequence data.

A compilation of data from the NIAID Influenza Genome Sequencing Project and GenBank. It provides tools for flu sequence analysis, annotation and submission to GenBank. This resource also has links to other flu sequence resources, and publications and general information about flu viruses.

A portal to information about medical genetics. MedGen includes term lists from multiple sources and organizes them into concept groupings and hierarchies. Links are also provided to information related to those concepts in the NIH Genetic Testing Registry (GTR), ClinVar,Gene, OMIM, PubMed, and other sources.

A project involving the collection and analysis of bacterial pathogen genomic sequences originating from food, environmental and patient isolates. Currently, an automated pipeline clusters and identifies sequences supplied primarily by public health laboratories to assist in the investigation of foodborne disease outbreaks and discover potential sources of food contamination.

A database of human genes and genetic disorders. NCBI maintains current content and continues to support its searching and integration with other NCBI databases. However, OMIM now has a new home at omim.org, and users are directed to this site for full record displays.

A database of citations and abstracts for biomedical literature from MEDLINE and additional life science journals. Links are provided when full text versions of the articles are available via PubMed Central (described below) or other websites.

A digital archive of full-text biomedical and life sciences journal literature, including clinical medicine and public health.

A collection of resources specifically designed to support the research of retroviruses, including a genotyping tool that uses the BLAST algorithm to identify the genotype of a query sequence; an alignment tool for global alignment of multiple sequences; an HIV-1 automatic sequence annotation tool; and annotated maps of numerous retroviruses viewable in GenBank, FASTA, and graphic formats, with links to associated sequence records.

A summary of data for the SARS coronavirus (CoV), including links to the most recent sequence data and publications, links to other SARS related resources, and a pre-computed alignment of genome sequences from various isolates.

An extension of the Influenza Virus Resource to other organisms, providing an interface to download sequence sets of selected viruses, analysis tools, including virus-specific BLAST pages, and genome annotation pipelines.

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Genetics & Medicine - Site Guide - NCBI - National Center for ...

Eli Lilly and Companyhas expanded alicencing and partnership agreement withProQR Therapeutics to discover, develop and market new genetic medicines.

The companies entered the initial agreement in September last year.

This alliance is utilising the Axiomer ribonucleic acid (RNA) editing platform of ProQR to address ailments affecting the liver and nervous system.

So far, progresses in the platform have substantially boosted editing efficiency and advanced biodistribution in the liver and nervous system.

This has also led to new possible applications to fix known mutations and to apply protective variants in particular transcripts.

Under the expanded partnership, the firms will analyse additional applications of the Axiomer platform to unveil new therapies for diseases with great unmet medical needs.

As per this deal, Lilly will obtain access to further targets in the central nervous system and peripheral nervous system using the Axiomer platform.

Lilly will make an upfront payment and equity investment totalling $75m to ProQR.

Additionally, Lilly holds the option to expand the collaboration for a fee worth $50m.

The company can also choose to grant ProQR access to its delivery technology for the fully owned pipeline.

As per the prior and expanded agreements, ProQR is entitled to get research, development and commercialisation milestone payments totalling up to nearly $3.75bn, apart from tiered royalty payments on sales of products.

ProQR founder and CEO Daniel de Boer said: Our original collaboration with Lilly, which leverages our Axiomer RNA editing technology platform, continues to progress well and we are pleased to be expanding our partnership to include additional targets, along with an option for Lilly to opt in for more.

The latest development comes after Lilly andSosei Heptaressigned a partnership for developing small moleculesthat modulate new G protein-coupled receptor targets linked to diabetes and metabolic diseases.

Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva.

Editorial content is independently produced and follows thehighest standardsof journalistic integrity. Topic sponsors are not involved in the creation of editorial content.

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Lilly, ProQR to expand genetic medicine development agreement

This interactive module uses the central dogma as a model for exploring how modern molecular biology technologies can be used to treat different genetic conditions.

The Click & Learn describes different steps in the pathways from gene to RNA to protein. It also provides information about a treatment strategy that targets each step, and an example of a genetic disease for which that strategy has been shown to work, either in experimental models or human clinical trials. The examples include treatments for cystic fibrosis, sickle cell disease, and Huntingtons disease, and are supplemented by video clips from the documentary The Gene Doctors, an HHMI Tangled Bank Studios Production.

The accompanying worksheet guides students exploration.

The Resource Google Folder link directs to a Google Drive folder of resource documents in the Google Docs format. Not all downloadable documents for the resource may be available in this format. The Google Drive folder is set as View Only; to save a copy of a document in this folder to your Google Drive, open that document, then select File Make a copy. These documents can be copied, modified, and distributed online following the Terms of Use listed in the Details section below, including crediting BioInteractive.

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Central Dogma and Genetic Medicine - HHMI BioInteractive

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Original post:
Social, Environmental, Cognitive, and Genetic Influences on the Use of ...

Controversies over GMO food

Genetically modified food controversies are disputes over the use of foods and other goods derived from genetically modified crops instead of conventional crops, and other uses of genetic engineering in food production. The disputes involve consumers, farmers, biotechnology companies, governmental regulators, non-governmental organizations, and scientists. The key areas of controversy related to genetically modified food (GM food or GMO food) are whether such food should be labeled, the role of government regulators, the objectivity of scientific research and publication, the effect of genetically modified crops on health and the environment, the effect on pesticide resistance, the impact of such crops for farmers, and the role of the crops in feeding the world population. In addition, products derived from GMO organisms play a role in the production of ethanol fuels and pharmaceuticals.

Specific concerns include mixing of genetically modified and non-genetically modified products in the food supply,[1] effects of GMOs on the environment,[2][3] the rigor of the regulatory process,[4][5] and consolidation of control of the food supply in companies that make and sell GMOs.[2] Advocacy groups such as the Center for Food Safety, Organic Consumers Association, Union of Concerned Scientists, and Greenpeace say risks have not been adequately identified and managed, and they have questioned the objectivity of regulatory authorities.

The safety assessment of genetically engineered food products by regulatory bodies starts with an evaluation of whether or not the food is substantially equivalent to non-genetically engineered counterparts that are already deemed fit for human consumption.[6][7][8][9] No reports of ill effects have been documented in the human population from genetically modified food.[10][11][12]

There is a scientific consensus[13][14][15][16] that currently available food derived from GM crops poses no greater risk to human health than conventional food,[17][18][19][20][21] but that each GM food needs to be tested on a case-by-case basis before introduction.[22][23][24] Nonetheless, members of the public are much less likely than scientists to perceive GM foods as safe,[25][26][27][28] The legal and regulatory status of GM foods varies by country, with some nations banning or restricting them and others permitting them with widely differing degrees of regulation.[29][30][31][32]

Consumer concerns about food quality first became prominent long before the advent of GM foods in the 1990s. Upton Sinclair's novel The Jungle led to the 1906 Pure Food and Drug Act, the first major US legislation on the subject.[33] This began an enduring concern over the purity and later "naturalness" of food that evolved from a single focus on sanitation to include others on added ingredients such as preservatives, flavors and sweeteners, residues such as pesticides, the rise of organic food as a category and, finally, concerns over GM food. Some consumers, including many in the US, came to see GM food as "unnatural", with various negative associations and fears (a reverse halo effect).[34]

Specific perceptions include a view of genetic engineering as meddling with naturally evolved biological processes, and one that science has limitations on its comprehension of potential negative ramifications.[35] An opposing perception is that genetic engineering is itself an evolution of traditional selective breeding, and that the weight of current evidence suggests current GM foods are identical to conventional foods in nutritional value and effects on health.[36][37]

Surveys indicate widespread concern among consumers that eating genetically modified food is harmful,[38][39][40] that biotechnology is risky, that more information is needed and that consumers need control over whether to take such risks.[41][41][42] A diffuse sense that social and technological change is accelerating, and that people cannot affect this context of change, becomes focused when such changes affect food.[41] Leaders in driving public perception of the harms of such food in the media include Jeffrey M. Smith, Dr. Oz, Oprah, and Bill Maher;[39][43] organizations include Organic Consumers Association,[44] Greenpeace (especially with regard to Golden rice)[45] and Union of Concerned Scientists.[40][46][47][48][49]

In the United States support or opposition or skepticism about GMO food is not divided by traditional partisan (liberal/conservative) lines, but young adults are more likely to have negative opinions on genetically modified food than older adults.[50]

Religious groups have raised concerns over whether genetically modified food will remain kosher or halal. In 2001, no such foods had been designated as unacceptable by Orthodox rabbis or Muslim leaders.[51]

Food writer Michael Pollan does not oppose eating genetically modified foods, but supports mandatory labeling of GM foods and has criticized the intensive farming enabled by certain GM crops, such as glyphosate-tolerant ("Roundup-ready") corn and soybeans.[52] He has also expressed concerns about biotechnology companies holding the intellectual property of the foods people depend on, and about the effects of the growing corporatization of large-scale agriculture.[53] To address these problems, Pollan has brought up the idea of open sourcing GM foods. The idea has since been adopted to varying degrees by companies like Syngenta,[54] and is being promoted by organizations such as the New America Foundation.[55] Some organizations, like The BioBricks Foundation, have already worked out open-source licenses that could prove useful in this endeavour.[56]

An EMBO Reports article in 2003 reported that the Public Perceptions of Agricultural Biotechnologies in Europe project (PABE)[57] found the public neither accepting nor rejecting GMOs. Instead, PABE found that public had "key questions" about GMOs: "Why do we need GMOs? Who benefits from their use? Who decided that they should be developed and how? Why were we not better informed about their use in our food, before their arrival on the market? Why are we not given an effective choice about whether or not to buy these products? Have potential long-term and irreversible consequences been seriously evaluated, and by whom? Do regulatory authorities have sufficient powers to effectively regulate large companies? Who wishes to develop these products? Can controls imposed by regulatory authorities be applied effectively? Who will be accountable in cases of unforeseen harm?"[26] PABE also found that the public's scientific knowledge does not control public opinion, since scientific facts do not answer these questions.[26] PABE also found that the public does not demand "zero risk" in GM food discussions and is "perfectly aware that their lives are full of risks that need to be counterbalanced against each other and against the potential benefits. Rather than zero risk, what they demanded was a more realistic assessment of risks by regulatory authorities and GMO producers."[26]

In 2006, the Pew Initiative on Food and Biotechnology made public a review of U.S. survey results between 2001 and 2006.[58] The review showed that Americans' knowledge of GM foods and animals was low throughout the period. Protests during this period against Calgene's Flavr Savr GM tomato mistakenly described it as containing fish genes, confusing it with DNA Plant Technology's fish tomato experimental transgenic organism, which was never commercialized.[59][60]

A survey in 2007 by the Food Standards Australia New Zealand found that in Australia, where labeling is mandatory,[61] 27% of Australians checked product labels to see whether GM ingredients were present when initially purchasing a food item.[62]

A review article about European consumer polls as of 2009 concluded that opposition to GMOs in Europe has been gradually decreasing,[63] and that about 80% of respondents did not "actively avoid GM products when shopping". The 2010 "Eurobarometer" survey,[64] which assesses public attitudes about biotech and the life sciences, found that cisgenics, GM crops made from plants that are crossable by conventional breeding, evokes a smaller reaction than transgenic methods, using genes from species that are taxonomically very different.[65] Eurobrometer survey in 2019 reported that most Europeans do not care about GMO when the topic is not presented explicitly, and when presented only 27% choose it as a concern. In just nine years since identical survey in 2010 the level of concern has halved in 28 EU Member States. Concern about specific topics decreased even more, for example genome editing on its own only concerns 4%.[66]

A Deloitte survey in 2010 found that 34% of U.S. consumers were very or extremely concerned about GM food, a 3% reduction from 2008.[67] The same survey found gender differences: 10% of men were extremely concerned, compared with 16% of women, and 16% of women were unconcerned, compared with 27% of men.

A poll by The New York Times in 2013 showed that 93% of Americans wanted labeling of GM food.[68]

The 2013 vote, rejecting Washington State's GM food labeling I-522 referendum came shortly after[69] the 2013 World Food Prize was awarded to employees of Monsanto and Syngenta.[70] The award has drawn criticism from opponents of genetically modified crops.[71][72][73][74]

With respect to the question of "Whether GMO foods were safe to eat", the gap between the opinion of the public and that of American Association for the Advancement of Science scientists is very wide with 88% of AAAS scientists saying yes in contrast to 37% of the general public.[75]

In May 2012, a group called "Take the Flour Back" led by Gerald Miles protested plans by a group from Rothamsted Experimental Station, based in Harpenden, Hertfordshire, England, to conduct an experimental trial wheat genetically modified to repel aphids.[76] The researchers, led by John Pickett, wrote a letter to the group in early May 2012, asking them to call off their protest, aimed for 27 May 2012.[77] Group member Lucy Harrap said that the group was concerned about spread of the crops into nature, and cited examples of outcomes in the United States and Canada.[78] Rothamsted Research and Sense About Science ran question and answer sessions about such a potential.[79]

The March Against Monsanto is an international grassroots movement and protest against Monsanto corporation, a producer of genetically modified organism (GMOs) and Roundup, a glyphosate-based herbicide.[80] The movement was founded by Tami Canal in response to the failure of California Proposition 37, a ballot initiative which would have required labeling food products made from GMOs. Advocates support mandatory labeling laws for food made from GMOs .[81]

The initial march took place on May 25, 2013. The number of protesters who took part is uncertain; figures of "hundreds of thousands" and the organizers' estimate of "two million"[82] were variously cited. Events took place in between 330[81] and 436[82] cities around the world, mostly in the United States.[81][83] Many protests occurred in Southern California, and some participants carried signs expressing support for mandatory labeling of GMOs that read "Label GMOs, It's Our Right to Know", and "Real Food 4 Real People".[83] Canal said that the movement would continue its "anti-GMO cause" beyond the initial event.[82] Further marches occurred in October 2013 and in May 2014 and 2015. The protests were reported by news outlets including ABC News,[84] the Associated Press,[82] The Washington Post,[85] The Los Angeles Times,[83] USA Today,[82] and CNN (in the United States), and The Guardian[80] (outside the United States).

Monsanto said that it respected people's rights to express their opinion on the topic, but maintained that its seeds improved agriculture by helping farmers produce more from their land while conserving resources, such as water and energy.[82] The company reiterated that genetically modified foods were safe and improved crop yields.[86] Similar sentiments were expressed by the Hawaii Crop Improvement Association, of which Monsanto is a member.[87][88]

In July 2013, the agricultural biotechnology industry launched a GMO transparency initiative called GMO Answers to address consumers' questions about GM foods in the U.S. food supply.[89] GMO Answers' resources included conventional and organic farmers, agribusiness experts, scientists, academics, medical doctors and nutritionists, and "company experts" from founding members of the Council for Biotechnology Information, which funds the initiative.[90] Founding members include BASF, Bayer CropScience, Dow AgroSciences, DuPont, Monsanto Company and Syngenta.[91]

In October 2013, a group called The European Network of Scientists for Social and Environmental Responsibility (ENSSER), posted a statement claiming that there is no scientific consensus on the safety of GMOs,[92] which was signed by about 200 scientists in various fields in its first week.[70] On January 25, 2015, their statement was formally published as a whitepaper by Environmental Sciences Europe:[93]

Earth Liberation Front, Greenpeace and others have disrupted GMO research around the world.[94][95][96][97][98] Within the UK and other European countries, as of 2014 80 crop trials by academic or governmental research institutes had been destroyed by protesters.[99] In some cases, threats and violence against people or property were carried out.[99] In 1999, activists burned the biotech lab of Michigan State University, destroying the results of years of work and property worth $400,000.[100]

In 1987, the ice-minus strain of P. syringae became the first genetically modified organism (GMO) to be released into the environment[101] when a strawberry field in California was sprayed with the bacteria. This was followed by the spraying of a crop of potato seedlings.[102] The plants in both test fields were uprooted by activist groups, but were re-planted the next day.[101]

In 2011, Greenpeace paid reparations when its members broke into the premises of an Australian scientific research organization, CSIRO, and destroyed a genetically modified wheat plot. The sentencing judge accused Greenpeace of cynically using junior members to avoid risking their own freedom. The offenders were given 9-month suspended sentences.[94][103][104]

On August 8, 2013 protesters uprooted an experimental plot of golden rice in the Philippines.[105][106] British author, journalist, and environmental activist Mark Lynas reported in Slate that the vandalism was carried out by a group led by the extreme-left Kilusang Magbubukid ng Pilipinas or Peasant Movement of the Philippines (KMP), to the dismay of other protesters.[107] Golden rice is designed to prevent vitamin A deficiency which, according to Helen Keller International, blinds or kills hundreds of thousands of children annually in developing countries.[108]

In 2017, two documentaries were released which countered the growing anti-GMO sentiment among the public. These included Food Evolution[109][110] and Science Moms. Per the Science Moms director, the film "focuses on providing a science and evidence-based counter-narrative to the pseudoscience-based parenting narrative that has cropped up in recent years".[111][112]

158 Nobel prize laureates in science have signed an open letter in 2016 in support of genetically modified farming and called for Greenpeace to cease its anti-scientific campaign, especially against the Golden Rice.[113]

There are various conspiracy theories related to the production and sale of genetically modified crops and genetically modified food that have been identified by some commentators such as Michael Shermer.[114] Generally, these conspiracy theories posit that GMOs are being knowingly and maliciously introduced into the food supply either as a means to unduly enrich agribusinesses or as a means to poison or pacify the population.

A work seeking to explore risk perception over GMOs in Turkey identified a belief among the conservative political and religious figures who were opposed to GMOs that GMOs were "a conspiracy by Jewish Multinational Companies and Israel for world domination."[115] Additionally, a Latvian study showed that a segment of the population believed that GMOs were part of a greater conspiracy theory to poison the population of the country.[116]

In 1983, environmental groups and protesters delayed the field tests of the genetically modified ice-minus strain of P. syringae with legal challenges.[117][118]

In this case, the plaintiff argued both for mandatory labeling on the basis of consumer demand, and that GMO foods should undergo the same testing requirements as food additives because they are "materially changed" and have potentially unidentified health risks. The plaintiff also alleged that the FDA did not follow the Administrative Procedures Act in formulating and disseminating its policy on GMO's. The federal district court rejected all of those arguments and found that the FDA's determination that GMO's are Generally Recognized as Safe was neither arbitrary nor capricious. The court gave deference to the FDA's process on all issues, leaving future plaintiffs little legal recourse to challenge the FDA's policy on GMO's.[49][119][120]

The Diamond v. Chakrabarty case was on the question of whether GMOs can be patented.

On 16 June 1980, the Supreme Court, in a 54 split decision, held that "A live, human-made micro-organism is patentable subject matter"[121] under the meaning of U.S. patent law.[122]

Scientific publishing on the safety and effects of GM foods is controversial.

One of the first incidents occurred in 1999, when Nature published a paper on potential toxic effects of Bt maize on butterflies. The paper produced a public uproar and demonstrations, however by 2001 multiple follow-up studies had concluded that "the most common types of Bt maize pollen are not toxic to monarch larvae in concentrations the insects would encounter in the fields" and that they had "brought that particular question to a close".[123]

Concerned scientists began to patrol the scientific literature and react strongly, both publicly and privately, to discredit conclusions they view as flawed in order to prevent unjustified public outcry and regulatory action.[123] A 2013 Scientific American article noted that a "tiny minority" of biologists have published concerns about GM food, and said that scientists who support the use of GMOs in food production are often overly dismissive of them.[124]

Prior to 2010, scientists wishing to conduct research on commercial GM plants or seeds were unable to do so, because of restrictive end-user agreements. Cornell University's Elson Shields was the spokesperson for one group of scientists who opposed such restrictions. The group submitted a statement to the United States Environmental Protection Agency (EPA) in 2009 protesting that "as a result of restrictive access, no truly independent research can be legally conducted on many critical questions regarding the technology".[125]

A 2009 Scientific American editorial quoted a scientist who said that several studies that were initially approved by seed companies were blocked from publication when they returned "unflattering" results. While favoring protection of intellectual property rights, the editors called for the restrictions to be lifted and for the EPA to require, as a condition of approval, that independent researchers have unfettered access to genetically modified products for research.[126]

In December 2009, the American Seed Trade Association agreed to "allow public researchers greater freedom to study the effects of GM food crops". The companies signed blanket agreements permitting such research. This agreement left many scientists optimistic about the future;[127] other scientists still express concern as to whether this agreement has the ability to "alter what has been a research environment rife with obstruction and suspicion".[125] Monsanto previously had research agreements (i.e., Academic Research Licenses) with approximately 100 universities that allowed for university scientists to conduct research on their GM products with no oversight.[128]

A 2011 analysis by Diels et al., reviewed 94 peer-reviewed studies pertaining to GMO safety to assess whether conflicts of interest correlated with outcomes that cast GMOs in a favorable light. They found that financial conflict of interest was not associated with study outcome (p = 0.631) while author affiliation to industry (i.e., a professional conflict of interest) was strongly associated with study outcome (p < 0.001).[129] Of the 94 studies that were analyzed, 52% did not declare funding. 10% of the studies were categorized as "undetermined" with regard to professional conflict of interest. Of the 43 studies with financial or professional conflicts of interest, 28 studies were compositional studies. According to Marc Brazeau, an association between professional conflict of interest and positive study outcomes can be skewed because companies typically contract with independent researchers to perform follow-up studies only after in-house research uncovers favorable results. In-house research that uncovers negative or unfavorable results for a novel GMO is generally not further pursued.[130]

A 2013 review, of 1,783 papers on genetically modified crops and food published between 2002 and 2012 found no plausible evidence of dangers from the use of then marketed GM crops.[13]

In a 2014 review, Zdziarski et al. examined 21 published studies of the histopathology of GI tracts of rats that were fed diets derived from GM crops, and identified some systemic flaws in this area of the scientific literature. Most studies were performed years after the approval of the crop for human consumption. Papers were often imprecise in their descriptions of the histological results and the selection of study endpoints, and lacked necessary details about methods and results. The authors called for the development of better study guidelines for determining the long-term safety of eating GM foods.[131]

A 2016 study by the US National Academies of Sciences, Engineering, and Medicine concluded that GM foods are safe for human consumption and they could find no conclusive evidence that they harm the environment nor wildlife.[132] They analysed over 1.000 studies over the previous 30 years that GM crops have been available, reviewed 700 written presentations submitted by interested bodies and heard 80 witnesses. They concluded that GM crops had given farmers economic advantages but found no evidence that GM crops had increased yields. They also noted that weed resistance to GM crops could cause major agricultural problems but this could be addressed by better farming procedures.[133]

A University of Naples investigation suggested that images in eight papers on animals were intentionally altered and/or misused. The leader of the research group, Federico Infascelli, rejected the claim. The research concluded that mother goats fed GM soybean meal secreted fragments of the foreign gene in their milk. In December 2015 one of the papers was retracted for "self-plagiarism", although the journal noted that the results remained valid.[134] A second paper was retracted in March 2016 after The University of Naples concluded that "multiple heterogeneities were likely attributable to digital manipulation, raising serious doubts on the reliability of the findings".[135]

There is a scientific consensus[13][14][15][16] that currently available food derived from GM crops poses no greater risk to human health than conventional food,[17][18][19][20][21] but that each GM food needs to be tested on a case-by-case basis before introduction.[22][23][24] Nonetheless, members of the public are much less likely than scientists to perceive GM foods as safe.[25][26][27][28] The legal and regulatory status of GM foods varies by country, with some nations banning or restricting them, and others permitting them with widely differing degrees of regulation.[29][30][31][32]

The ENTRANSFOOD project was a European Commission-funded scientist group chartered to set a research program to address public concerns about the safety and value of agricultural biotechnology.[136] It concluded that "the combination of existing test methods provides a sound test-regime to assess the safety of GM crops."[137] In 2010, the European Commission Directorate-General for Research and Innovation reported that "The main conclusion to be drawn from the efforts of more than 130 research projects, covering a period of more than 25 years of involving more than 500 independent research groups, is that biotechnology, and in particular GMOs, are not per se more risky than e.g. conventional plant breeding technologies."[138]:16

Consensus among scientists and regulators pointed to the need for improved testing technologies and protocols.[11][139] Transgenic and cisgenic organisms are treated similarly when assessed. However, in 2012 the European Food Safety Authority (EFSA) GMO Panel said that "novel hazards" could be associated with transgenic strains.[140] In a 2016 review, Domingo concluded that studies in recent years had established that GM soybeans, rice, corn, and wheat do not differ from the corresponding conventional crops in terms of short-term human health effects, but recommended that further studies of long-term effects be conducted.[141]

Most conventional agricultural products are the products of genetic manipulation via traditional cross-breeding and hybridization.[142][137][143]

Governments manage the marketing and release of GM foods on a case-by-case basis. Countries differ in their risk assessments and regulations. Marked differences distinguish the US from Europe. Crops not intended as foods are generally not reviewed for food safety.[144] GM foods are not tested in humans before marketing because they are not a single chemical, nor are they intended to be ingested using specific doses and intervals, which complicate clinical study design.[8] Regulators examine the genetic modification, related protein products and any changes that those proteins make to the food.[145]

Regulators check that GM foods are "substantially equivalent" to their conventional counterparts, to detect any negative unintended consequences.[6][7][8] New protein(s) that differ from conventional food proteins or anomalies that arise in the substantial equivalence comparison require further toxicological analysis.[8]

"The World Health Organization, the American Medical Association, the U.S. National Academy of Sciences, the British Royal Society, and every other respected organization that has examined the evidence has come to the same conclusion: consuming foods containing ingredients derived from GM crops is no riskier than consuming the same foods containing ingredients from crop plants modified by conventional plant improvement techniques."

American Association for the Advancement of Science[146]

In 1999, Andrew Chesson of the Rowett Research Institute warned that substantial equivalence testing "could be flawed in some cases" and that current safety tests could allow harmful substances to enter the human food supply.[147] The same year Millstone, Brunner and Mayer argued that the standard was a pseudo-scientific product of politics and lobbying that was created to reassure consumers and aid biotechnology companies to reduce the time and cost of safety testing. They suggested that GM foods have extensive biological, toxicological and immunological tests and that substantial equivalence should be abandoned.[148] This commentary was criticized for misrepresenting history,[149] for distorting existing data and poor logic.[150] Kuiper claimed that it oversimplified safety assessments and that equivalence testing involves more than chemical tests, possibly including toxicity testing.[9][151] Keler and Lappe supported Congressional legislation to replace the substantial equivalence standard with safety studies.[152] In a 2016 review, Domingo criticized the use of the "substantial equivalence" concept as a measure of the safety of GM crops.[153]

Kuiper examined this process further in 2002, finding that substantial equivalence does not measure absolute risks, but instead identifies differences between new and existing products. He claimed that characterizing differences is properly a starting point for a safety assessment[9] and "the concept of substantial equivalence is an adequate tool in order to identify safety issues related to genetically modified products that have a traditional counterpart". Kuiper noted practical difficulties in applying this standard, including the fact that traditional foods contain many toxic or carcinogenic chemicals and that existing diets were never proven to be safe. This lack of knowledge re conventional food means that modified foods may differ in anti-nutrients and natural toxins that have never been identified in the original plant, possibly allowing harmful changes to be missed.[9] In turn, positive modifications may also be missed. For example, corn damaged by insects often contains high levels of fumonisins, carcinogenic toxins made by fungi that travel on insects' backs and that grow in the wounds of damaged corn. Studies show that most Bt corn has lower levels of fumonisins than conventional insect-damaged corn.[154][155] Workshops and consultations organized by the OECD, WHO, and FAO have worked to acquire data and develop better understanding of conventional foods, for use in assessing GM foods.[139][156]

A survey of publications comparing the intrinsic qualities of modified and conventional crop lines (examining genomes, proteomes and metabolomes) concluded that GM crops had less impact on gene expression or on protein and metabolite levels than the variability generated by conventional breeding.[157]

In a 2013 review, Herman (Dow AgroSciences) and Price (FDA, retired) argued that transgenesis is less disruptive than traditional breeding techniques because the latter routinely involve more changes (mutations, deletions, insertions and rearrangements) than the relatively limited changes (often single gene) in genetic engineering. The FDA found that all of the 148 transgenic events that they evaluated to be substantially equivalent to their conventional counterparts, as have Japanese regulators for 189 submissions including combined-trait products. This equivalence was confirmed by more than 80 peer-reviewed publications. Hence, the authors argue, compositional equivalence studies uniquely required for GM food crops may no longer be justified on the basis of scientific uncertainty.[158]

A well-known risk of genetic modification is the introduction of an allergen. Allergen testing is routine for products intended for food, and passing those tests is part of the regulatory requirements. Organizations such as the European Green Party and Greenpeace emphasize this risk.[159] A 2005 review of the results from allergen testing stated that "no biotech proteins in foods have been documented to cause allergic reactions".[160] Regulatory authorities require that new modified foods be tested for allergenicity before they are marketed.[161]

GMO proponents note that because of the safety testing requirements, the risk of introducing a plant variety with a new allergen or toxin is much smaller than from traditional breeding processes, which do not require such tests. Genetic engineering can have less impact on the expression of genomes or on protein and metabolite levels than conventional breeding or (non-directed) plant mutagenesis.[157] Toxicologists note that "conventional food is not risk-free; allergies occur with many known and even new conventional foods. For example, the kiwi fruit was introduced into the U.S. and the European markets in the 1960s with no known human allergies; however, today there are people allergic to this fruit."[6]

Genetic modification can also be used to remove allergens from foods, potentially reducing the risk of food allergies.[162] A hypo-allergenic strain of soybean was tested in 2003 and shown to lack the major allergen that is found in the beans.[163] A similar approach has been tried in ryegrass, which produces pollen that is a major cause of hay fever: here a fertile GM grass was produced that lacked the main pollen allergen, demonstrating that hypoallergenic grass is also possible.[164]

The development of genetically modified products found to cause allergic reactions has been halted by the companies developing them before they were brought to market. In the early 1990s, Pioneer Hi-Bred attempted to improve the nutrition content of soybeans intended for animal feed by adding a gene from the Brazil nut. Because they knew that people have allergies to nuts, Pioneer ran in vitro and skin prick allergy tests. The tests showed that the transgenic soy was allergenic.[165] Pioneer Hi-Bred therefore discontinued further development.[166][167] In 2005, a pest-resistant field pea developed by the Australian Commonwealth Scientific and Industrial Research Organisation for use as a pasture crop was shown to cause an allergic reaction in mice.[168] Work on this variety was immediately halted. These cases have been used as evidence that genetic modification can produce unexpected and dangerous changes in foods, and as evidence that safety tests effectively protect the food supply.[12]

During the Starlink corn recalls in 2000, a variety of GM maize containing the Bacillus thuringiensis (Bt) protein Cry9C, was found contaminating corn products in U.S. supermarkets and restaurants. It was also found in Japan and South Korea.[169]:2021 Starlink corn had only been approved for animal feed as the Cry9C protein lasts longer in the digestive system than other Bt proteins raising concerns about its potential allergenicity.[170]:3 In 2000, Taco Bell-branded taco shells sold in supermarkets were found to contain Starlink, resulting in a recall of those products, and eventually led to the recall of over 300 products.[171][172][173] Sales of StarLink seed were discontinued and the registration for the Starlink varieties was voluntarily withdrawn by Aventis in October 2000.[174] Aid sent by the United Nations and the United States to Central African nations was also found to be contaminated with StarLink corn and the aid was rejected. The U.S. corn supply has been monitored for Starlink Bt proteins since 2001 and no positive samples have been found since 2004.[175] In response, GeneWatch UK and Greenpeace set up the GM Contamination Register in 2005.[176] During the recall, the United States Centers for Disease Control evaluated reports of allergic reactions to StarLink corn, and determined that no allergic reactions to the corn had occurred.[177][178]

Horizontal gene transfer is the movement of genes from one organism to another in a manner other than reproduction.

The risk of horizontal gene transfer between GMO plants and animals is very low and in most cases is expected to be lower than background rates.[179] Two studies on the possible effects of feeding animals with genetically modified food found no residues of recombinant DNA or novel proteins in any organ or tissue samples.[180][181] Studies found DNA from the M13 virus, Green fluorescent protein and RuBisCO genes in the blood and tissue of animals,[182][183] and in 2012, a paper suggested that a specific microRNA from rice could be found at very low quantities in human and animal serum.[184] Other studies[185][186] however, found no or negligible transfer of plant microRNAs into the blood of humans or any of three model organisms.

Another concern is that the antibiotic resistance gene commonly used as a genetic marker in transgenic crops could be transferred to harmful bacteria, creating resistant superbugs.[187][188] A 2004 study involving human volunteers examined whether the transgene from modified soy would transfer to bacteria that live in the human gut. As of 2012 it was the only human feeding study to have been conducted with GM food. The transgene was detected in three volunteers from a group of seven who had previously had their large intestines removed for medical reasons. As this gene transfer did not increase after the consumption of the modified soy, the researchers concluded that gene transfer did not occur. In volunteers with intact digestive tracts, the transgene did not survive.[189] The antibiotic resistance genes used in genetic engineering are naturally found in many pathogens[190] and antibiotics these genes confer resistance to are not widely prescribed.[191]

Reviews of animal feeding studies mostly found no effects. A 2014 review found that the performance of animals fed GM feed was similar to that of animals fed "isogenic non-GE crop lines".[192] A 2012 review of 12 long-term studies and 12 multigenerational studies conducted by public research laboratories concluded that none had discovered any safety problems linked to consumption of GM food.[193] A 2009 review by Magaa-Gmez found that although most studies concluded that modified foods do not differ in nutrition or cause toxic effects in animals, some did report adverse changes at a cellular level caused by specific modified foods. The review concluded that "More scientific effort and investigation is needed to ensure that consumption of GM foods is not likely to provoke any form of health problem".[194] Dona and Arvanitoyannis' 2009 review concluded that "results of most studies with GM foods indicate that they may cause some common toxic effects such as hepatic, pancreatic, renal, or reproductive effects and may alter the hematological, biochemical, and immunologic parameters".[195] Reactions to this review in 2009 and 2010 noted that Dona and Arvanitoyannis had concentrated on articles with an anti-modification bias that were refuted in peer-reviewed articles elsewhere.[196][197][198] Flachowsky concluded in a 2005 review that food with a one-gene modification were similar in nutrition and safety to non-modified foods, but he noted that food with multiple gene modifications would be more difficult to test and would require further animal studies.[180] A 2004 review of animal feeding trials by Aumaitre and others found no differences among animals eating genetically modified plants.[199]

In 2007, Domingo's search of the PubMed database using 12 search terms indicated that the "number of references" on the safety of GM or transgenic crops was "surprisingly limited", and he questioned whether the safety of GM food had been demonstrated. The review also stated that its conclusions were in agreement with three earlier reviews.[200] However, Vain found 692 research studies in 2007 that focused on GM crop and food safety and found increasing publication rates of such articles in recent years.[201][202] Vain commented that the multidisciplinarian nature of GM research complicated the retrieval of studies based on it and required many search terms (he used more than 300) and multiple databases. Domingo and Bordonaba reviewed the literature again in 2011 and said that, although there had been a substantial increase in the number of studies since 2006, most were conducted by biotechnology companies "responsible of commercializing these GM plants."[203] In 2016, Domingo published an updated analysis, and concluded that as of that time there were enough independent studies to establish that GM crops were not any more dangerous acutely than conventional foods, while still calling for more long-term studies.[204]

While some groups and individuals have called for more human testing of GM food,[205] multiple obstacles complicate such studies. The General Accounting Office (in a review of FDA procedures requested by Congress) and a working group of the Food and Agriculture and World Health organizations both said that long-term human studies of the effect of GM food are not feasible. The reasons included lack of a plausible hypothesis to test, lack of knowledge about the potential long-term effects of conventional foods, variability in the ways humans react to foods and that epidemiological studies were unlikely to differentiate modified from conventional foods, which come with their own suite of unhealthy characteristics.[206][207]

Additionally, ethical concerns guide human subject research. These mandate that each tested intervention must have a potential benefit for the human subjects, such as treatment for a disease or nutritional benefit (ruling out, e.g., human toxicity testing).[208] Kimber claimed that the "ethical and technical constraints of conducting human trials, and the necessity of doing so, is a subject that requires considerable attention."[209] Food with nutritional benefits may escape this objection. For example, GM rice has been tested for nutritional benefits, namely, increased levels of Vitamin A.[210][211]

rpd Pusztai published the first peer-reviewed paper to find negative effects from GM food consumption in 1999. Pusztai fed rats potatoes transformed with the Galanthus nivalis agglutinin (GNA) gene from the Galanthus (snowdrop) plant, allowing the tuber to synthesise the GNA lectin protein.[212] While some companies were considering growing GM crops expressing lectin, GNA was an unlikely candidate.[213] Lectin is toxic, especially to gut epithelia.[214] Pusztai reported significant differences in the thickness of the gut epithelium, but no differences in growth or immune system function.[212][215]

On June 22, 1998, an interview on Granada Television's current affairs programme World in Action, Pusztai said that rats fed on the potatoes had stunted growth and a repressed immune system.[216] A media frenzy resulted. Pusztai was suspended from the Rowett Institute. Misconduct procedures were used to seize his data and ban him from speaking publicly.[217] The Rowett Institute and the Royal Society reviewed his work and concluded that the data did not support his conclusions.[218][219][12] The work was criticized on the grounds that the unmodified potatoes were not a fair control diet and that any rat fed only potatoes would suffer from protein deficiency.[220] Pusztai responded by stating that all diets had the same protein and energy content and that the food intake of all rats was the same.

A 2011 study was the first to evaluate the correlation between maternal and fetal exposure to Bt toxin produced in GM maize and to determine exposure levels of the pesticides and their metabolites. It reported the presence of pesticides associated with the modified foods in women and in pregnant women's fetuses.[221] The paper and related media reports were criticized for overstating the results.[222][223] Food Standards Australia New Zealand (FSANZ) posted a direct response, saying that the suitability of the ELISA method for detecting the Cry1Ab protein was not validated and that no evidence showed that GM food was the protein's source. The organization also suggested that even had the protein been detected its source was more likely conventional or organic food.[224]

In 2007, 2009, and 2011, Gilles-ric Sralini published re-analysis studies that used data from Monsanto rat-feeding experiments for three modified maize varieties (insect-resistant MON 863 and MON 810 and glyphosate-resistant NK603). He concluded that the data showed liver, kidney and heart damage.[225][226][227] The European Food Safety Authority (EFSA) then concluded that the differences were all within the normal range.[228] EFSA also stated that Sralini's statistics were faulty.[229][230][231] EFSA's conclusions were supported by FSANZ,[232][233][234] a panel of expert toxicologists,[235] and the French High Council of Biotechnologies Scientific Committee (HCB).[236]

In 2012, Sralini's lab published a paper[237][238] that considered the long-term effects of feeding rats various levels of GM glyphosate-resistant maize, conventional glyphosate-treated maize, and a mixture of the two strains.[239] The paper concluded that rats fed the modified maize had severe health problems, including liver and kidney damage and large tumors.[239] The study provoked widespread criticism. Sralini held a press conference just before the paper was released in which he announced the release of a book and a movie.[240] He allowed reporters to have access to the paper before his press conference only if they signed a confidentiality agreement under which they could not report other scientists' responses to the paper.[241] The press conference resulted in media coverage emphasizing a connection between GMOs, glyphosate, and cancer.[242] Sralini's publicity stunt yielded criticism from other scientists for prohibiting critical commentary.[242][243][244] Criticisms included insufficient statistical power[245] and that Sralini's Sprague-Dawley rats were inappropriate for a lifetime study (as opposed to a shorter toxicity study) because of their tendency to develop cancer (one study found that more than 80% normally got cancer).[246][247][248][249] The Organisation for Economic Co-operation and Development guidelines recommended using 65 rats per experiment instead of the 10 in Sralini's.[248][249][250] Other criticisms included the lack of data regarding food amounts and specimen growth rates,[251][252] the lack of a doseresponse relationship (females fed three times the standard dose showed a decreased number of tumours)[253] and no identified mechanism for the tumour increases.[254] Six French national academies of science issued an unprecedented joint statement condemning the study and the journal that published it.[255] Food and Chemical Toxicology published many critical letters, with only a few expressing support.[256] National food safety and regulatory agencies also reviewed the paper and dismissed it.[257][258][259][260][261][262][263][264] In March 2013, Sralini responded to these criticisms in the same journal that originally published his study,[265] and a few scientists supported his work.[124]:5 In November 2013, the editors of Food and Chemical Toxicology retracted the paper.[237][238] The retraction was met with protests from Sralini and his supporters.[266][267] In 2014, the study was republished by a different journal, Environmental Sciences Europe, in an expanded form, including the raw data that Sralini had originally refused to reveal.[268]

Some plants are specifically genetically modified to be healthier than conventional crops. Golden rice was created to combat vitamin A deficiency by synthesizing beta carotene (which conventional rice does not).[269]

One variety of cottonseed has been genetically modified to remove the toxin gossypol, so that it would be safe for humans to eat.[270]

Genetically modified crops are planted in fields much like regular crops. There they interact directly with organisms that feed on the crops and indirectly with other organisms in the food chain. The pollen from the plants is distributed in the environment like that of any other crop. This distribution has led to concerns over the effects of GM crops on the environment. Potential effects include gene flow/genetic pollution, pesticide resistance and greenhouse gas emissions.

A major use of GM crops is in insect control through the expression of the cry (crystal delta-endotoxins) and Vip (vegetative insecticidal proteins) genes from Bacillus thuringiensis (Bt). Such toxins could affect other insects in addition to targeted pests such as the European corn borer. Bt proteins have been used as organic sprays for insect control in France since 1938 and the US since 1958, with no reported ill effects.[271] Cry proteins selectively target Lepidopterans (moths and butterflies). As a toxic mechanism, cry proteins bind to specific receptors on the membranes of mid-gut (epithelial) cells, resulting in their rupture. Any organism that lacks the appropriate receptors in its gut is unaffected by the cry protein, and therefore is not affected by Bt.[272][273] Regulatory agencies assess the potential for transgenic plants to affect non-target organisms before approving their commercial release.[274][275]

In 1999, a paper stated that, in a laboratory environment, pollen from Bt maize dusted onto milkweed could harm the monarch butterfly.[276] A collaborative research exercise over the following two years by several groups of scientists in the US and Canada studied the effects of Bt pollen in both the field and the laboratory. The study resulted in a risk assessment concluding that any risk posed to butterfly populations was negligible.[277] A 2002 review of the scientific literature concluded that "the commercial large-scale cultivation of current Btmaize hybrids did not pose a significant risk to the monarch population" and noted that despite large-scale planting of genetically modified crops, the butterfly's population was increasing.[278] However, the herbicide glyphosate used to grow GMOs kills milkweed, the only food source of monarch butterflies, and by 2015 about 90% of the U.S. population has declined.[279][280]

Lvei et al. analyzed laboratory settings and found that Bt toxins could affect non-target organisms, generally closely related to the intended targets.[281] Typically, exposure occurs through the consumption of plant parts, such as pollen or plant debris, or through Bt ingestion by predators. A group of academic scientists criticized the analysis, writing: "We are deeply concerned about the inappropriate methods used in their paper, the lack of ecological context, and the authors' advocacy of how laboratory studies on non-target arthropods should be conducted and interpreted".[282]

Crop genetic diversity might decrease due to the development of superior GM strains that crowd others out of the market. Indirect effects might affect other organisms. To the extent that agrochemicals impact biodiversity, modifications that increase their use, either because successful strains require them or because the accompanying development of resistance will require increased amounts of chemicals to offset increased resistance in target organisms.

Studies comparing the genetic diversity of cotton found that in the US diversity has either increased or stayed the same, while in India it has declined. This difference was attributed to the larger number of modified varieties in the US compared to India.[283] A review of the effects of Bt crops on soil ecosystems found that in general they "appear to have no consistent, significant, and long-term effects on the microbiota and their activities in soil".[284]

The diversity and number of weed populations has been shown to decrease in farm-scale trials in the United Kingdom and in Denmark when comparing herbicide-resistant crops to their conventional counterparts.[285][286] The UK trial suggested that the diversity of birds could be adversely affected by the decrease in weed seeds available for foraging.[287] Published farm data involved in the trials showed that seed-eating birds were more abundant on conventional maize after the application of the herbicide, but that there were no significant differences in any other crop or prior to herbicide treatment.[288] A 2012 study found a correlation between the reduction of milkweed in farms that grew glyphosate-resistant crops and the decline in adult monarch butterfly populations in Mexico.[289] The New York Times reported that the study "raises the somewhat radical notion that perhaps weeds on farms should be protected.[290]

A 2005 study, designed to "simulate the impact of a direct overspray on a wetland" with four different agrochemicals (carbaryl (Sevin), malathion, 2,4-dichlorophenoxyacetic acid, and glyphosate in a Roundup formulation) by creating artificial ecosystems in tanks and then applying "each chemical at the manufacturer's maximum recommended application rates" found that "species richness was reduced by 15% with Sevin, 30% with malathion, and 22% with Roundup, whereas 2,4-D had no effect".[291] The study has been used by environmental groups to argue that use of agrochemicals causes unintended harm to the environment and to biodiversity.[292]

Several studies documented surges in secondary pests within a few years of adoption of Bt cotton. In China, the main problem has been with mirids,[293][294] which have in some cases "completely eroded all benefits from Bt cotton cultivation".[295] A 2009 study in China concluded that the increase in secondary pests depended on local temperature and rainfall conditions and occurred in half the villages studied. The increase in insecticide use for the control of these secondary insects was far smaller than the reduction in total insecticide use due to Bt cotton adoption.[296] A 2011 study based on a survey of 1,000 randomly selected farm households in five provinces in China found that the reduction in pesticide use in Bt cotton cultivars was significantly lower than that reported in research elsewhere: The finding was consistent with a hypothesis that more pesticide sprayings are needed over time to control emerging secondary pests, such as aphids, spider mites, and lygus bugs.[297] Similar problems have been reported in India, with mealy bugs[298][299] and aphids.[300]

Genes from a GMO may pass to another organism just like an endogenous gene. The process is known as outcrossing and can occur in any new open-pollinated crop variety. As late as the 1990s this was thought to be unlikely and rare, and if it were to occur, easily eradicated. It was thought that this would add no additional environmental costs or risks - no effects were expected other than those already caused by pesticide applications. Introduced traits potentially can cross into neighboring plants of the same or closely related species through three different types of gene flow: crop-to-crop, crop-to-weedy, and crop-to-wild.[301] In crop-to-crop, genetic information from a genetically modified crop is transferred to a non-genetically modified crop. Crop-to-weedy transfer refers to the transfer of genetically modified material to a weed, and crop-to-wild indicates transfer from a genetically modified crop to a wild, undomesticated plant and/or crop.[302] There are concerns that the spread of genes from modified organisms to unmodified relatives could produce species of weeds resistant to herbicides[303] that could contaminate nearby non-genetically modified crops, or could disrupt the ecosystem,[304][305] This is primarily a concern if the transgenic organism has a significant survival capacity and can increase in frequency and persist in natural populations.[306] This process, whereby genes are transferred from GMOs to wild relatives, is different from the development of so-called "superweeds" or "superbugs" that develop resistance to pesticides under natural selection.

In most countries environmental studies are required before approval of a GMO for commercial purposes, and a monitoring plan must be presented to identify unanticipated gene flow effects.

In 2004, Chilcutt and Tabashnik found Bt protein in kernels of a refuge crop (a conventional crop planted to harbor pests that might otherwise become resistant a pesticide associated with the GMO) implying that gene flow had occurred.[307]

In 2005, scientists at the UK Centre for Ecology and Hydrology reported the first evidence of horizontal gene transfer of pesticide resistance to weeds, in a few plants from a single season; they found no evidence that any of the hybrids had survived in subsequent seasons.[308]

In 2007, the U.S. Department of Agriculture fined Scotts Miracle-Gro $500,000 when modified DNA from GM creeping bentgrass, was found within relatives of the same genus (Agrostis)[309] as well as in native grasses up to 21km (13mi) from the test sites, released when freshly cut, wind-blown grass.[310]

In 2009, Mexico created a regulatory pathway for GM maize,[311] but because Mexico is maize's center of diversity, concerns were raised about GM maize's effects on local strains.[312][313] A 2001 report found Bt maize cross-breeding with conventional maize in Mexico.[314] The data in this paper was later described as originating from an artifact and the publishing journal Nature stated that "the evidence available is not sufficient to justify the publication of the original paper", although it did not retract the paper.[315] A subsequent large-scale study, in 2005, found no evidence of gene flow in Oaxaca.[316] However, other authors claimed to have found evidence of such gene flow.[317]

A 2010 study showed that about 83 percent of wild or weedy canola tested contained genetically modified herbicide resistance genes.[318][319][320] According to the researchers, the lack of reports in the United States suggested that oversight and monitoring were inadequate.[321] A 2010 report stated that the advent of glyphosate-resistant weeds could cause GM crops to lose their effectiveness unless farmers combined glyphosate with other weed-management strategies.[322][323]

One way to avoid environmental contamination is genetic use restriction technology (GURT), also called "Terminator".[324] This uncommercialized technology would allow the production of crops with sterile seeds, which would prevent the escape of GM traits. Groups concerned about food supplies had expressed concern that the technology would be used to limit access to fertile seeds.[325][326] Another hypothetical technology known as "Traitor" or "T-GURT", would not render seeds sterile, but instead would require application of a chemical to GM crops to activate engineered traits.[324][327] Groups such as Rural Advancement Foundation International raised concerns that further food safety and environmental testing needed to be done before T-GURT would be commercialized.[327]

The escape of genetically modified seed into neighboring fields, and the mixing of harvested products, is of concern to farmers who sell to countries that do not allow GMO imports.[328]:275[329]

In 1999 scientists in Thailand claimed they had discovered unapproved glyphosate-resistant GM wheat in a grain shipment, even though it was only grown in test plots. No mechanism for the escape was identified.[330]

In 2000, Aventis StarLink GM corn was found in US markets and restaurants. It became the subject of a recall that started when Taco Bell-branded taco shells sold in supermarkets were found to contain it. StarLink was then discontinued.[171][172] Registration for Starlink varieties was voluntarily withdrawn by Aventis in October 2000.[174]

American rice exports to Europe were interrupted in 2006 when the LibertyLink modification was found in commercial rice crops, although it had not been approved for release.[331] An investigation by the USDA's Animal and Plant Health Inspection Service (APHIS) failed to determine the cause of the contamination.[332]

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Genetically modified food controversies - Wikipedia

Closing Date: 30/10/2022Location: Oxford Genetics Laboratory

The Oxford Genetics Laboratories (OGL) have a rare and exciting opportunity for an individual with relevant experience to join us as a Principal Clinical Scientist in Bioinformatics. OGL works in partnership with West Midlands and Wessex laboratories to form the Central & South Genomic Laboratory Hub (C&SGLH), and provides state-of-the-art molecular and cytogenetic diagnostic testing for core and specialist rare disease services, and for acquired disorders. We undertake a comprehensive range of investigations that includes NGS analysis using in-house pipelines, and WGS interpretation. OGL also collaborates closely with many of the genetic research leaders in Oxford, as well as the NIHR Oxford Biomedical Research Centre. The successful candidate will lead a small Bioinformatics team and contribute to the overall management and direction of the OGL, particularly with regards to data security. Additionally, you will participate in C&SGLH and NHSE bioinformatic forums to inform the OGL bioinformatic strategy, and may take on other relevant professional roles, for example in training. We are keen to hear from Registered Clinical Bioinformaticians, as well as from people with relevant transferrable skills who have worked in the private sector or academia. This is a permanent full-time post (37.5hrs) but applicants wishing to work part-time will be considered. The OGL is open 8am to 6pm Monday to Friday, and the working pattern is expected to be within these times. The Principal Bioinformatician undertakes a broad range of bioinformatic, analytical and administrative duties with a considerable degree of autonomy, assuming responsibility for all aspects of the bioinformatic services including developing and implementing a robust bioinformatics strategy to meet the needs of a large multi-disciplinary laboratory. They will also ensure secure yet accessible data storage, and be responsible for laboratory-wide organisation, monitoring, co-ordination and achievement of specific bioinformatic targets, with responsibility for all bioinformatic staff within the department. They are required to ensure delivery of a computational framework that has the flexibility and robustness to deliver expert analysis of complex data generated using the latest sequencing technologies, and will perform highly accurate and skilled analysis with often unpredictable outcomes and requiring periods of intense concentration. The role involves continued development of bioinformatics strategy and requires networking with peers and a deep understanding of the molecular biology and computational processes of NGS data generation. He/she must be able to effectively trouble-shoot any potential data quality issues, and communicate complex bioinformatic, scientific and confidential information to colleagues in electronic, written and verbal forms. Bioinformaticians also participate in teaching and training and are expected to remain up-to-date with their field.

Carl FratterEmail: Carl.Fratter@ouh.nhs.ukWebsite: http://jobs.ouh.nhs.uk/job/v4528933

Genetics Laboratory, Churchill HopsitalOxfordOxonOX3 7LE

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BSGM - The British Society for Genetic Medicine

Services We Offer

Services we offer include:

Learn More About Our Services

A genetics consult starts with a phone call from a genetic counseling assistant. The assistant will gather information about the reason for the visit, obtain a detailed history of any problems in the family (which is called a pedigree) and possibly request medical records from other providers or hospitals. Sometimes, the assistant may need sensitive information. During this first contact, if you do not want to come for a full visit or have concerns about sharing sensitive information, please let us know.

The first appointment will take about two hours.If the person who is referred is a child, they MUST come to the visit. Plan to arrive at least 30 minutes before your appointment time to allow ample time to get registered, complete forms and have measurements taken (height, weight, blood pressure).

You will meet with several healthcare providers at this visit. This will include a genetic counselor, a genetic nurse practitioner or genetics physician, and possibly a metabolic dietician.

A consult with genetics is more than having genetic testing. It includes a full assessment that consists of taking a detailed history, reviewing outside medical records and performing a complete exam. We will discuss possible conditions, provide genetic counseling and review what may be needed to establish a diagnosis. A decision about whether testing is required, and what kind of tests should be performed, will be discussed at the first visit.

In most cases, testing will not be done at that time. If testing is recommended, we will work with your insurance to get prior authorization and let you know when to return for testing.

A return visit with the nurse practitioner, geneticist or genetic counselor is often needed when test results are available. Our team will go over what the results mean and discuss any next steps. Genetic counseling will be provided at every step to ensure you understand what the results mean for the patient and the family. Finally, any needed additional tests will be ordered, and a care plan with specific treatments, if available, will be made.

Clinical services are supported partly by the Ohio Department of Health as a Regional Genetics Center of the State of Ohio, Region IV.

Kim L. McBride, MD, MS, is Division Chief of Genetic and Genomic Medicine at Nationwide Children's Hospital.

Murugu Manickam, MD, MPH, FACMG, is Section Chief of Genetic and Genomic Medicine at Nationwide Children's Hospital.

Genetics ClinicTower Building, 4th Floor, Suite D700 Children's DriveColumbus, OH 43205(614) 722-3535FAX (614) 722-3546Metabolic ClinicTower Building, 4th Floor, Suite D700 Childrens DriveColumbus, OH 43205(614) 722-3543FAX (614) 722-3546Dublin Genetics ClinicDublin Medical Office Building5665 Venture DriveDublin, OH 43017(614) 722-3535FAX (614) 722-3546Tuesdays all day

Westerville Genetics ClinicClose To Home Center on N. Cleveland AvenueWesterville, OH 43082(614) 722-3535FAX (614) 722-3546Mondays 12:30 pm 5:00pm

Athens Outreach278 W. Union StreetAthens, OH 45701To schedule, call: (614) 592-4431FAX (614) 594-9929Held bimonthly on a Wednesday

Marietta OutreachMarietta City Health Department304 Putnam StreetMarietta, OH 45750To schedule, call: (740) 373-0611FAX (740) 376-2008Held bimonthly on a Wednesday

Waverly OutreachPike County General Health District14050 US23 NWaverly, Ohio 45690To schedule, call: (614) 722-3535Fax referral to: (614) 722-3546Office Phone: (740) 947-7721Office Fax (740) 947-1109Held bimonthly on a Wednesday

Zanesville OutreachMuskingham Valley Health Care719 Adair AvenueZanesville, Ohio 43701To schedule, call: (614) 722-3535Fax referral to: (614) 722-3546Held bimonthly on a Wednesday

22q CenterNationwide Childrens Hospital700 Childrens DriveColumbus, OH 43205(614) 722-6200FAX (614) 722-4000Office phone (614) 962-6373

Complex Epilepsy Clinic (Epilepsy Center)Nationwide Childrens Hospital700 Childrens DriveColumbus, OH 43205(614) 722-6200FAX (614) 722-4000

Cleft Lip and Palate CenterNationwide Childrens Hospital700 Children's DriveSuite T5EColumbus, Ohio 43205(614) 722-6200FAX (614) 722-4000Office phone (614) 962-6366Tues. 12:30 pm 5 pm

Cystic Fibrosis ClinicOutpatient Care Center, 5th Floor555 S. 18th StreetColumbus, OH 43205Phone: (614) 722-4766Fax: (614) 722-4755Tues PM, Wed PM, and Thurs PM

Down Syndrome Clinic (Developmental and Behavioral Pediatrics)Nationwide Childrens Hospital700 Childrens DriveColumbus, OH 43205(614) 722-6200FAX (614) 722-4000Office phone (614) 722-4050

Muscular Dystrophy Association(MDA)/Spinal Muscular Atrophy (SMA) ClinicOutpatient Care Center, 1st Floor555 S. 18th StreetColumbus, OH 43205(614) 722-6200FAX (614) 722-4000Office phone (614) 722-2203Wednesdays

Myelomeningocele Clinic (Developmental and Behavioral Pediatrics)Nationwide Childrens Hospital700 Childrens DriveColumbus, OH 43205(614) 722-6200FAX (614) 722-4000Office phone (614) 722-4050Friday AM

Prader-Willi Syndrome Clinic (Endocrinology)Outpatient Care Center, 5th Floor555 S. 18th StreetColumbus, OH 43205(614) 722-6200FAX (614) 722-4000Office phone (614) 722-44252nd Friday of the month

Williams Syndrome Clinic (Developmental and Behavioral Pediatrics)Nationwide Childrens Hospital700 Childrens DriveColumbus, OH 43205(614) 722-6200FAX (614) 722-4000Office phone (614) 722-40502nd Tuesday of the month

The mission of the Center for Gene Therapy is to investigate and employ the use of gene- and cell-based therapeutics for prevention and treatment of human diseases.

The Center for Cardiovascular Research conducts innovative research leading to improved therapies and outcomes for pediatric cardiovascular diseases and promotes cardiovascular health in adults.

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Genetic and Genomic Medicine - Nationwide Children's Hospital

Number 691 (Replaces Committee Opinion Number 318, October 2005; Committee Opinion Number 432, May 2009; Committee Opinion Number 442, October 2009; Committee Opinion Number 469, October 2010; Committee Opinion Number 486, April 2011. Reaffirmed 2020)

Committee on Genetics

This Committee Opinion was developed by the American College of Obstetricians and Gynecologists Committee on Genetics in collaboration with committee members Britton Rink, MD; Stephanie Romero, MD; Joseph R. Biggio Jr, MD; Devereux N. Saller Jr, MD; and Rose Giardine, MS.

This document reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed.

ABSTRACT: Carrier screening is a term used to describe genetic testing that is performed on an individual who does not have any overt phenotype for a genetic disorder but may have one variant allele within a gene(s) associated with a diagnosis. Information about carrier screening should be provided to every pregnant woman. Carrier screening and counseling ideally should be performed before pregnancy because this enables couples to learn about their reproductive risk and consider the most complete range of reproductive options. A patient may decline any or all screening. When an individual is found to be a carrier for a genetic condition, his or her relatives are at risk of carrying the same mutation. The patient should be encouraged to inform his or her relatives of the risk and the availability of carrier screening. If an individual is found to be a carrier for a specific condition, the patients reproductive partner should be offered testing in order to receive informed genetic counseling about potential reproductive outcomes. If both partners are found to be carriers of a genetic condition, genetic counseling should be offered. What follows is a detailed discussion of some of the more common genetic conditions for which carrier screening is recommended in at least some segments of the population.

The American College of Obstetricians and Gynecologists (the College) makes the following recommendations and conclusions:

Information about genetic carrier screening should be provided to every pregnant woman. After counseling, a patient may decline any or all screening.

Carrier screening and counseling ideally should be performed before pregnancy.

If an individual is found to be a carrier for a specific condition, the individuals reproductive partner should be offered testing in order to receive informed genetic counseling about potential reproductive outcomes. Concurrent screening of the patient and her partner is suggested if there are time constraints for decisions about prenatal diagnostic evaluation.

If both partners are found to be carriers of a genetic condition, genetic counseling should be offered. Prenatal diagnosis and advanced reproductive technologies to decrease the risk of an affected offspring should be discussed.

When an individual is found to be a carrier for a genetic condition, the individuals relatives are at risk of carrying the same mutation. The patient should be encouraged to inform his or her relatives of the risk and the availability of carrier screening. The obstetriciangynecologist or other health care provider should not disclose this information without permission from the patient.

It is important to obtain the family history of the patient and, if possible, her partner as a screening tool for inherited risk. The family history should include the ethnic background of family members as well as any known consanguinity. Individuals with a positive family history of a genetic condition should be offered carrier screening for the specific condition and may benefit from genetic counseling.

Carrier screening for a particular condition generally should be performed only once in a persons lifetime, and the results should be documented in the patients health record. Because of the rapid evolution of genetic testing, additional mutations may be included in newer screening panels. The decision to rescreen a patient should be undertaken only with the guidance of a genetics professional who can best assess the incremental benefit of repeat testing for additional mutations.

Prenatal carrier screening does not replace newborn screening, nor does newborn screening replace the potential value of prenatal carrier screening.

If a patient requests carrier screening for a particular condition for which testing is readily available and which reasonably would be considered in another screening strategy, the requested test should be offered to her (regardless of ethnicity and family history) after counseling on the risks, benefits, and limitations of screening.

The cost of carrier screening for an individual condition may be higher than the cost of testing through commercially available expanded carrier screening panels. When selecting a carrier screening approach, the cost of each option to the patient and the health care system should be considered.

Screening for spinal muscular atrophy should be offered to all women who are considering pregnancy or are currently pregnant.

In patients with a family history of spinal muscular atrophy, molecular testing reports of the affected individual and carrier testing of the related parent should be reviewed, if possible, before testing. If the reports are not available, SMN1 deletion testing should be recommended for the low-risk partner.

Cystic fibrosis carrier screening should be offered to all women who are considering pregnancy or are currently pregnant.

Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening.

For couples in which both partners are unaffected but one or both has a family history of cystic fibrosis, genetic counseling and medical record review should be performed to determine if CFTR mutation analysis in the affected family member is available.

If a womans reproductive partner has cystic fibrosis or apparently isolated congenital bilateral absence of the vas deferens, the couple should be provided follow-up genetic counseling by an obstetriciangynecologist or other health care provider with expertise in genetics for mutation analysis and consultation.

A complete blood count with red blood cell indices should be performed in all women who are currently pregnant to assess not only their risk of anemia but also to allow assessment for risk of a hemoglobinopathy. Ideally, this testing also should be offered to women before pregnancy.

A hemoglobin electrophoresis should be performed in addition to a complete blood count if there is suspicion of hemoglobinopathy based on ethnicity (African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent). If red blood cell indices indicate a low mean corpuscular hemoglobin or mean corpuscular volume, hemoglobin electrophoresis also should be performed.

Fragile X premutation carrier screening is recommended for women with a family history of fragile X-related disorders or intellectual disability suggestive of fragile X syndrome and who are considering pregnancy or are currently pregnant.

If a woman has unexplained ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40 years, fragile X carrier screening is recommended to determine whether she has an FMR1 premutation.

All identified individuals with intermediate results and carriers of a fragile X premutation or full mutation should be provided follow-up genetic counseling to discuss the risk to their offspring of inheriting an expanded full-mutation fragile X allele and to discuss fragile X-associated disorders (premature ovarian insufficiency and fragile X tremor/ataxia syndrome).

Prenatal diagnostic testing for fragile X syndrome should be offered to known carriers of the fragile X premutation or full mutation.

DNA-based molecular analysis (eg, Southern blot analysis and polymerase chain reaction) is the preferred method of diagnosis of fragile X syndrome and of determining FMR1 triplet repeat number (eg, premutations). In rare cases, the size of the triplet repeat and the methylation status do not correlate, which makes it difficult to predict the clinical phenotype. In cases of this discordance, the patient should be referred to a genetics professional.

When only one partner is of Ashkenazi Jewish descent, that individual should be offered screening first. If it is determined that this individual is a carrier, the other partner should be offered screening. However, the couple should be informed that the carrier frequency and the detection rate in non-Jewish individuals are unknown for most of these disorders, except for TaySachs disease and cystic fibrosis. Therefore, it is difficult to accurately predict the couples risk of having a child with the disorder.

Screening for TaySachs disease should be offered when considering pregnancy or during pregnancy if either member of a couple is of Ashkenazi Jewish, FrenchCanadian, or Cajun descent. Those with a family history consistent with TaySachs disease also should be offered screening.

When one member of a couple is at high risk (ie, of Ashkenazi Jewish, FrenchCanadian, or Cajun descent or has a family history consistent with TaySachs disease) but the other partner is not, the high-risk partner should be offered screening. If the high-risk partner is found to be a carrier, the other partner also should be offered screening.

Enzyme testing in pregnant women and women taking oral contraceptives should be performed using leukocyte testing because serum testing is associated with an increased false-positive rate in these populations.

If TaySachs disease screening is performed as part of pan-ethnic expanded carrier screening, it is important to recognize the limitations of the mutations screened in detecting carriers in the general population. In the presence of a family history of TaySachs disease, expanded carrier screening panels are not the best approach to screening unless the familial mutation is included on the panel.

Referral to an obstetriciangynecologist or other health care provider with genetics expertise may be helpful in instances of inconclusive enzyme testing results or in discussion of carrier testing of an individual with non-Ashkenazi Jewish ethnicity whose reproductive partner is a known carrier of TaySachs disease.

Carrier screening is a term used to describe genetic testing that is performed on an individual who does not have any overt phenotype for a genetic disorder but may have one variant allele within a gene(s) associated with a diagnosis. Information about genetic carrier screening should be provided to every pregnant woman. After counseling, a patient may decline any or all screening. Carrier screening and counseling ideally should be performed before pregnancy because this enables couples to learn about their reproductive risk and consider the most complete range of reproductive options, including whether or not to become pregnant and whether to use advanced reproductive technologies such as preimplantation genetic diagnosis or use of donor gametes. Knowledge during pregnancy allows patients to consider prenatal diagnosis and pregnancy management options in the event of an affected fetus.

If an individual is found to be a carrier for a specific condition, the individuals reproductive partner should be offered testing in order to receive informed genetic counseling about potential reproductive outcomes. Concurrent screening of the patient and her partner is suggested if there are time constraints for decisions about prenatal diagnostic evaluation. If both partners are found to be carriers of a genetic condition, genetic counseling should be offered. Prenatal diagnosis and advanced reproductive technologies to decrease the risk of an affected offspring should be discussed. Prenatal carrier screening does not replace newborn screening, nor does newborn screening replace the potential value of prenatal carrier screening.

When an individual is found to be a carrier for a genetic condition, the individuals relatives are at risk of carrying the same mutation. The patient should be encouraged to inform his or her relatives of the risk and the availability of carrier screening. The obstetriciangynecologist or other health care provider should not disclose this information without permission from the patient.

It is important to obtain the family history of the patient and, if possible, her partner as a screening tool for inherited risk. The family history should include the ethnic background of family members as well as any known consanguinity (a union between two individuals who are second cousins or closer in family relationship) 1*. Individuals with a positive family history of a genetic condition should be offered carrier screening for the specific condition and may benefit from genetic counseling. Ideally, information on the specific mutation will be available to aid testing and counseling.

Carrier screening for a particular condition generally should be performed only once in a persons lifetime, and the results should be documented in the patients health record. Because of the rapid evolution of genetic testing, additional mutations may be included in newer screening panels. The decision to rescreen a patient should be undertaken only with the guidance of a genetics professional who can best assess the incremental benefit of repeat testing for additional mutations.

Although several different strategies for screening are available and reviewed in Committee Opinion No. 690,Carrier Screening in the Age of Genomic Medicine, this document seeks to provide information about the different conditions for which a patient may seek prepregnancy carrier screening. If a patient requests carrier screening for a particular condition for which testing is readily available and which reasonably would be considered in another screening strategy, the requested test should be offered to her (regardless of ethnicity and family history) after counseling on the risks, benefits, and limitations of screening. The cost of carrier screening for an individual condition may be higher than the cost of testing through commercially available expanded carrier screening panels. When selecting a carrier screening approach, the cost of each option to the patient and the health care system should be considered.

What follows is a detailed discussion of some of the more common genetic conditions for which carrier screening is recommended in at least some segments of the population. The different sections collect topics that had previously been discussed in separate Committee Opinions to show how the aforementioned general principles are used and reflected in carrier screening for specific genetic conditions.

Spinal muscular atrophy, also known as SMA, is an autosomal recessive disease characterized by degeneration of spinal cord motor neurons that leads to atrophy of skeletal muscle and overall weakness. The disorder is caused by a mutation in the gene known as the survival motor neuron gene (SMN1), which is responsible for the production of a protein essential to motor neuron function. Because of the severity and relatively high carrier frequency, there has been increasing interest in carrier screening for spinal muscular atrophy in the general prenatal population 3. The genetics of spinal muscular atrophy are complex and, because of limitations in the molecular diagnostic assays available, precise prediction of the phenotype in affected fetuses may not be possible.

The incidence of spinal muscular atrophy is approximately 1 in 6,000 to 1 in 10,000 live births, and the disease is reported to be the leading genetic cause of infant death. Carrier frequencies in most populations are estimated at 1 in 40 to 1 in 60, but carrier frequencies appear to be lower in the Hispanic population (1:117) 4. Carrier frequencies and residual risks are outlined by ethnicity in Table 1. Approximately 2% of cases of spinal muscular atrophy are the result of a new gene mutation. There is no effective treatment for the disease.

There are several types of spinal muscular atrophy based on age at symptom onset. Earlier onset is correlated with more severe manifestations. The most severe and most common form of the disease, type I (WerdnigHoffman), has symptomatic onset before 6 months of age and causes death from respiratory failure within the first 2 years of life. Type II spinal muscular atrophy is of intermediate severity, with typical onset before 2 years of age. Affected children are able to sit, but few are able to stand or walk unaided. Respiratory insufficiency is a frequent cause of death during adolescence; however, the lifespan of patients with spinal muscular atrophy type II varies from age 2 years to the third decade of life. More than 80% of cases of spinal muscular atrophy are type I or type II, both of which are lethal forms. A milder form, type III (KugelbergWelander), has typical symptomatic onset after 18 months of age. However, the symptom profile is quite variable. Affected individuals typically reach all major motor milestones, but function ranges from requiring wheelchair assistance in childhood to completely unaided ambulation into adulthood with minor muscular weakness. Many patients have normal life expectancies. Type IV has onset in adulthood. There is an additional Type 0 proposed, which has onset in the prenatal period.

There are two nearly identical survival motor neuron genes present in humans, known as SMN1 and SMN2. SMN1 is considered the active gene for survival motor neuron protein production, and more than 98% of patients with spinal muscular atrophy have an abnormality in both SMN1 genes, which can be caused by a deletion (95%) of exon 7, or other mutation. There is generally one copy of SMN1 per chromosome, but occasionally two can be located on the same chromosome. A variable number of SMN2 gene copies (ranging from zero to three) may be present, but the SMN2 gene produces only a small amount of functional survival motor neuron protein. A higher number of SMN2 copies correlates with generally milder clinical phenotypes, but accurate prediction of the spinal muscular atrophy phenotype based on SMN2 copy number is not possible 5.

For diagnosis of spinal muscular atrophy in a child or an adult, it is sufficient to simply detect the classic SMN1 deletion using DNA analysis in both SMN1 alleles. This is approximately 95% sensitive (100% specific) for patients with clinical features suspicious for spinal muscular atrophy. However, this approach is not sufficient to identify patients who are heterozygous, or carriers, for the SMN1 deletion. Carrier testing requires a quantitative polymerase chain reaction assay that provides a measure of SMN1 copy number. Detection of a single normal copy of SMN1 would indicate the carrier state Figure 1. There are limitations, however, to the use of this assay to determine carrier status. Approximately 34% of the general population have two SMN1 copies on one chromosome and no copies on the other and will not be identified as being a carrier of spinal muscular atrophy using this approach. These individuals are carriers because one of their chromosomes is missing the SMN1 allele. The missing SMN1 allele appears to be more predominant in African Americans and lowers the carrier detection rate to approximately 71% in this group. In other ethnic groups, more than 90% of carriers are detected by dosage analysis of SMN1. Another 2% of the general population has SMN1 mutations that are not detectable by dosage analysis. Therefore, the counseling of patients who are tested for carrier status must account for the residual risk present when carrier screening assay results are negative, particularly in patients from families affected by spinal muscular atrophy.

Screening for spinal muscular atrophy should be offered to all women who are considering pregnancy or are currently pregnant and have had appropriate counseling about the possible range of severity, carrier rate, and detection rate. Posttest counseling should reiterate residual risk after negative screening based on the number of SMN1 copies present. In patients with a family history of spinal muscular atrophy, molecular testing reports of the affected individual and carrier testing of the related parent should be reviewed, if possible, before testing to determine the residual risk for the patient with a negative screen. If the reports are not available, SMN1 deletion testing should be recommended for the low-risk partner. If this individual is found to be a carrier, the couple should be referred for further genetic counseling and consideration of further genetic testing in the high-risk partner.

Prepregnancy and prenatal carrier screening for cystic fibrosis, also known as CF, was introduced into routine obstetric practice in 2001 6. The goal of cystic fibrosis carrier screening is to identify individuals at risk of having a child with classic cystic fibrosis, which is defined by significant pulmonary disease and pancreatic insufficiency. Cystic fibrosis is more common among the non-Hispanic white population compared with other racial and ethnic populations; however, because of the increasing difficulty in assigning a single ethnicity to individuals, in 2005, the American College of Obstetricians and Gynecologists recommended offering cystic fibrosis carrier screening to all patients.

Cystic fibrosis is the most common life-threatening, autosomal recessive condition in the non-Hispanic white population. The disease incidence is 1 in 2,500 individuals in the non-Hispanic white population and considerably less in other ethnic groups. It is a progressive, multisystem disease that primarily affects the pulmonary, pancreatic, and gastrointestinal systems but does not affect intelligence. The current median predicted survival is approximately 42 years, with respiratory failure as the most common cause of death 7. More than 95% of males with cystic fibrosis have primary infertility with obstructive azoospermia secondary to congenital bilateral absence of the vas deferens. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, located on chromosome 7. Two copies of deleterious mutations in this gene cause cystic fibrosis.

The sensitivity of the screening test varies among ethnic groups Table 2, ranging from less than 50% in those of Asian ancestry to 94% in the Ashkenazi Jewish population 8. Therefore, screening is most efficacious in non-Hispanic white and Ashkenazi Jewish populations. Because screening is offered for only the most common mutations, a negative screening test result reduces but does not eliminate the chance of being a cystic fibrosis carrier and having an affected offspring. Therefore, if a patient is screened for cystic fibrosis and has a negative test result, she still has a residual risk of being a carrier. The most common cystic fibrosis carrier frequencies, as well as the rates of residual carrier risk after a negative test result, are listed by racial and ethnic group in Table 2.

As with all carrier screening, it is generally more cost effective and practical to perform initial carrier screening only for the patient. Cystic fibrosis carrier screening should be offered to all women who are considering pregnancy or are currently pregnant. If the patient is a cystic fibrosis carrier, then her partner should be tested. During pregnancy, concurrent screening of the patient and her partner is suggested if there are time constraints for decisions regarding prenatal diagnostic evaluation. Given that cystic fibrosis screening has been a routine part of reproductive care for women since 2001, it is prudent to determine if the patient has been previously screened before ordering repeat cystic fibrosis screening. If a patient has been screened previously, cystic fibrosis screening results should be documented, but the test should not be repeated. Although some mutation panels have been expanded over the past decade, the incremental yield of the addition of those mutations is small for most patients. Before repeat testing, the clinical scenario should be discussed with an obstetriciangynecologist or other health care provider with expertise in genetics.

The following are various carrier screening scenarios with associated management recommendations:

A woman is a carrier of a cystic fibrosis mutation and her partner is unavailable for testing or paternity is unknown. Genetic counseling to review the risk of having an affected child and prenatal testing options and limitations is recommended.

Prenatal diagnosis is being performed for other indications and cystic fibrosis carrier status is unknown. Cystic fibrosis screening can be performed concurrently on the patient and partner. Chorionic villi or amniocytes may be maintained in culture by the diagnostic laboratory until cystic fibrosis screening results are available for the patient or couple. If both partners are carriers, diagnostic testing for cystic fibrosis can be performed on the chorionic villi or amniocytes.

Both partners are cystic fibrosis carriers. Genetic counseling is recommended to review prenatal testing and reproductive options. Prenatal diagnosis should be offered for the couples specific, known mutations.

Both partners are unaffected, but one or both has a family history of cystic fibrosis. Genetic counseling and medical record review should be performed to determine if CFTR mutation analysis in the affected family member is available. Carrier screening should be offered for both partners, with attention to ensure that the familial mutation is included in the assessment.

A womans reproductive partner has cystic fibrosis or apparently isolated congenital bilateral absence of the vas deferens. The couple should be provided follow-up genetic counseling by an obstetriciangynecologist or other health care provider with expertise in genetics for mutation analysis and consultation.

An individual has two cystic fibrosis mutations but has not previously received a diagnosis of cystic fibrosis. The individual usually has a mild form of the disease and should be referred to a specialist for further evaluation. Genetic counseling is recommended.

To date, more than 1,700 mutations have been identified for cystic fibrosis 9. Current guidelines, revised by the American College of Medical Genetics and Genomics in 2004, recommend use of a panel that contains, at a minimum, the 23 most common mutations. The guidelines were developed after assessing the initial experiences following the implementation of cystic fibrosis screening into clinical practice 10. A number of expanded mutation panels are now commercially available and can be considered to enhance the sensitivity for carrier detection, especially in non-Caucasian ethnic groups. Cystic fibrosis screening also may identify the 5T/7T/9T variants in the CFTR gene. Although not disease-causing on their own, these variants can be associated with milder forms of disease and male infertility in individuals who are heterozygous for certain CFTR gene mutations. Genetic counseling is important to discern whether the combination of mutations and variants would cause classic or atypical cystic fibrosis.

Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening. This type of testing generally is reserved for patients with cystic fibrosis, patients with negative carrier screening result but a family history of cystic fibrosis (especially if family test results are not available), males with congenital bilateral absence of the vas deferens, or newborns with a positive newborn screening result when mutation testing (using the standard 23-mutation panel) has a negative result. Because carrier screening detects most mutations, sequence analysis should be considered only after discussion with a genetics professional to determine if it will add value to the standard screening that was performed previously.

All states include cystic fibrosis screening as part of their newborn screening panel. However, newborn screening panels do not replace prepregnancy or prenatal carrier screening. Because these screening programs generally identify affected newborns, a negative test result in an unaffected newborn provides no information about the carrier status of the parents. Thus, it is important that cystic fibrosis screening continues to be offered to women who are considering pregnancy or are currently pregnant.

Hemoglobin consists of four interlocking polypeptide chains, each of which has an attached heme molecule. Adult hemoglobin consists of two -chains and either two-chains (hemoglobin A), two -chains (hemoglobin F), or two -chains (hemoglobin A2). Alpha-globin chain production begins in the first trimester and is an essential component of fetal hemoglobin F, hemoglobin A, and hemoglobin A2. Hemoglobin F is the primary hemoglobin of the fetus from 12 weeks to 24 weeks of gestation. In the third trimester, production of hemoglobin F decreases as production of -chains and hemoglobin A begins.

Sickle cell disease refers to a group of autosomal recessive disorders that involve abnormal hemoglobin (hemoglobin S). Hemoglobin S differs from the normal hemoglobin A because of a single nucleotide substitution in the -globin gene; this alteration causes a substitution of valine for glutamic acid in the number six position of the -globin polypeptide. Asymptomatic individuals with heterozygous hemoglobin S genotypes (carriers) are said to have sickle cell trait. The most severe form of the disease, hemoglobin SS (homozygous hemoglobin S), is called sickle cell anemia.

Sickle cell disorders are found not only in patients who have the hemoglobin genotype SS, but also in those who have hemoglobin S and another abnormality of -globin structure or -globin production. The most common of these are hemoglobin SC disease and hemoglobin S/-thalassemia. In hemoglobin C, the same nucleotide involved in the hemoglobin S mutation is altered, but the nucleotide change results in the amino acid substitution of lysine for glutamic acid. This and other abnormal hemoglobins, when inherited with hemoglobin S, may cause clinically significant vasoocclusive phenomena and hemolytic anemia similar to hemoglobin SS.

Sickle cell disease occurs most commonly in people of African origin. Approximately 1 in 10 African Americans has sickle cell trait 11. One in every 300500 African-American newborns has some form of sickle cell disease. Hemoglobin S also is found in high frequency in other populations such as Greeks, Italians (particularly Sicilians), Turks, Arabs, Southern Iranians, and Asian Indians 12.

The classical clinical feature of patients with sickle cell disease is seen under conditions of decreased oxygen tension, in which the red blood cells become distorted into various shapes, some of which resemble sickles. The distorted red cells lead to increased viscosity, hemolysis, and anemia and a further decrease in oxygenation. When sickling occurs within small blood vessels, it can interrupt blood supply to vital organs (vasoocclusive crisis).Repeated vasoocclusive crises result in widespread microvascular obstruction with interruption of normal perfusion and function of several organs, including the spleen, lungs, kidneys, heart, and brain. These crises are extremely painful and typically require hospitalization and medical management. Over the course of their lifetimes, patients with sickle cell disease who have repeated crises often build up tolerance to opioid medications and may require large doses in order to achieve relief from the pain of an acute vasoocclusive crisis. Also, these patients often have an element of chronic pain and they may require daily pain medication even in the absence of an acute crisis. Adults with hemoglobin SS are functionally asplenic, having undergone autosplenectomy by adolescence. Absence of the spleen contributes to the increased incidence and severity of infection in patients with sickle cell disease.

The most significant threat to patients with sickle cell disease is acute chest syndrome. Acute chest syndrome is characterized by a pulmonary infiltrate with fever that leads to hypoxemia and acidosis. The infiltrates are not infectious in origin but rather are due to vasoocclusion from sickling or embolization of marrow from long bones affected by sickling 13.

The diagnosis of hemoglobinopathies, including sickle cell disorders, is made by hemoglobin electrophoresis. In the homozygous form of sickle cell disease, nearly all the hemoglobin is hemoglobin S with small amounts of hemoglobin A2 and hemoglobin F. Heterozygous sickle cell trait (hemoglobin AS) is identified by a larger percentage of hemoglobin A and an asymptomatic course. Solubility tests alone are inadequate for diagnosis of sickle cell disorders because they cannot distinguish between the heterozygous AS and homozygous SS genotypes. Solubility tests are not useful for screening because of the inability to identify other pathologic variants such as hemoglobin C, hemoglobin E, and -thalassemia trait.

The thalassemias represent a wide spectrum of hematologic disorders that are characterized by a reduced synthesis of globin chains, which results in microcytic anemia. Thalassemias are classified according to the globin chain affected, with the most common types being -thalassemia and -thalassemia 14.

Alpha-thalassemia usually results from a gene deletion of two or more copies of the four -globin genes. Deletion of one -globin gene (-/) is clinically unrecognizable, and laboratory testing yields normal results. Deletion of two -globin genes causes -thalassemia trait, a mild asymptomatic microcytic anemia. The deletions can be on the same chromosome or in cis (/--), or on each chromosome or in trans (--).

Individuals with these gene deletions are referred to as carriers and are at an increased risk of having children with a more severe form of thalassemia caused by deletions of three or four copies of the -globin gene (-thalassemia major). The possible genetic combinations are summarized in Table 3.

Alpha-thalassemia trait (-thalassemia minor) is common among individuals of Southeast Asian, African, and West Indian descent and in individuals with Mediterranean ancestry. Individuals with Southeast Asian ancestry are more likely to carry two gene deletions in cis or on the same chromosome (--) and are at an increased risk of offspring with hemoglobin Bart or hemoglobin H disease. Hemoglobin H disease, which is caused by the deletion of three -globin genes, usually is associated with mild-to-moderate hemolytic anemia. Alpha-thalassemia major (hemoglobin Bart) results in the absence of -globin (--/--), which is associated with hydrops fetalis, intrauterine death, and preeclampsia 12.

Beta-thalassemia is the result of a mutation in the -globin gene that causes deficient or absent -chain production, which in turn causes an absence of hemoglobin A. Individuals of Mediterranean, Asian, Middle Eastern, Hispanic, and West Indian descent are more likely to carry -thalassemia mutations. Classification of -thalassemias is based on a description of the molecular mutation or on clinical manifestations. Individuals who are heterozygous for this mutation have -thalassemia minor. Those who are homozygous have -thalassemia major (Cooleys anemia) or a milder form called thalassemia intermedia. There are numerous mutations associated with -thalassemia, and each mutation can have a different effect on the amount of -chain produced. Because of the many different mutations, many individuals with -thalassemia major are actually compound heterozygotes carrying two different mutations. Beta-thalassemia major is characterized by severe anemia with resultant extramedullary erythropoiesis, delayed sexual development, and poor growth. Elevated levels of hemoglobin F in individuals with -thalassemia major partially compensate for the absence of hemoglobin A; however, death usually occurs by age 10 years unless treatment is begun early with periodic blood transfusions. With transfusion, the severe anemia is reversed and extramedullary erythropoiesis is suppressed. In homozygotes with the less severe +-thalassemia mutations, often referred to as -thalassemia intermedia, variable but decreased amounts of -chains are produced and as a result variable amounts of hemoglobin A are produced. Some individuals can inherit a hemoglobin S mutation from one parent and a -thalassemia mutation from the other. The expression of the resulting hemoglobin S/-thalassemia is determined by the type of -thalassemia mutation 15.

A combination of laboratory tests may be required to provide the information necessary to counsel couples who are carriers of one of the thalassemias or sickle cell disease. To ensure accurate hemoglobin identification, which is essential for genetic counseling, a complete blood count with red blood cell indices should be performed in all women who are currently pregnant to assess not only their risk of anemia but also to allow assessment for risk of a hemoglobinopathy. If red blood cell indices indicate a low mean corpuscular hemoglobin or mean corpuscular volume, hemoglobin electrophoresis also should be performed. A hemoglobin electrophoresis should be performed in addition to a complete blood count if there is suspicion of hemoglobinopathy based on ethnicity (African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent). Ideally, this testing also should be offered to women before pregnancy. If the results of a prior hemoglobin electrophoresis are available, repeat hemoglobin electrophoresis is not necessary to evaluate status.

Several tests, including solubility testing (such as a test for the presence of hemoglobin S), isoelectric focusing, and high-performance liquid chromatography, have been used for primary screening. However, solubility tests are inadequate for screening and fail to identify important transmissible hemoglobin gene abnormalities that affect fetal outcome (eg, hemoglobin C trait, -thalassemia trait, hemoglobin E trait). Many individuals with these genotypes are asymptomatic, but if their partners have the sickle cell trait or other hemoglobinopathies, they may produce offspring with more serious hemoglobinopathies, such as hemoglobin S/-thalassemia and hemoglobin sickle cell disease.

Determination of mean corpuscular volume is recommended to assess risk of -thalassemia or -thalassemia. Patients who have a low mean corpuscular volume (less than 80 fL) may have one of the thalassemia traits, and hemoglobin electrophoresis should be performed if it was not done previously. These individuals also may have iron deficiency anemia, and measurement of serum ferritin levels is recommended. Beta-thalassemia is associated with elevated hemoglobin F and elevated hemoglobin A2 levels (more than 3.5%). Neither hemoglobin electrophoresis nor solubility testing can identify individuals with -thalassemia trait; only molecular genetic testing can identify this condition. If the mean corpuscular volume is below normal, iron deficiency anemia has been excluded, and the hemoglobin electrophoresis is not consistent with -thalassemia trait (ie, there is no elevation of Hb A2 or Hb F), then DNA-based testing should be used to detect -globin gene deletions characteristic of-thalassemia. The hematologic features of some of the common hemoglobinopathies are shown in Table 4. If both partners are identified as carriers of a gene for abnormal hemoglobins, genetic counseling is recommended.

Couples at risk of having a child with a hemoglobinopathy may benefit from genetic counseling to review their risk, the natural history of these disorders, prospects for treatment and cure, availability of prenatal genetic testing, and reproductive options. Prenatal diagnostic testing for the mutation responsible for sickle cell disease is widely available. Testing for -thalassemia and -thalassemia is possible if the mutations and deletions have been previously identified in both parents. These DNA-based tests can be performed using chorionic villi obtained by chorionic villus sampling or using cultured amniotic fluid cells obtained by amniocentesis. For some couples, preimplantation genetic diagnosis in combination with in vitro fertilization may be a desirable alternative to avoid termination of an affected pregnancy. Preimplantation genetic diagnosis has been successfully performed for sickle cell disease and most types of -thalassemia.

Fragile X syndrome is the most common inherited form of intellectual disability. The syndrome occurs in approximately 1 in 3,600 males and 1 in 4,0006,000 females from a variety of ethnic backgrounds. Intellectual disability or impairment ranges from borderline, including learning disabilities, to severe, presenting with cognitive and behavioral disabilities, including autism with intellectual disability; attention deficithyperactivity disorder; or both. Most affected males have significant intellectual disability. Fragile X syndrome is a common known cause of autism or autism spectrum disorder behaviors with intellectual disability, with the diagnosis occurring in approximately 25% of affected individuals 16. Other associated phenotypic abnormalities include distinctive facial features in males (including a long, narrow face and prominent ears), enlarged testicles (macroorchidism), joint and skin laxity, hypotonia, mitral valve prolapse, delay in speech, and delay in gross and fine motor skills. The abnormal facial features are subtle in infancy and become more noticeable with age, making phenotypic diagnosis difficult, especially in the newborn. Affected females may have a milder phenotype, and it is sometimes hard to establish the diagnosis based on clinical findings alone.

Fragile X syndrome is transmitted as an X-linked disorder. However, the molecular genetics of the syndrome are complex. The disorder is caused by expansion of a repeated trinucleotide segment of DNA, cytosineguanineguanine that leads to altered transcription of the fragile X gene FMR1. The number of cytosineguanineguanine repeats varies among individuals and has been classified into four groups depending on the repeat size: 1) unaffected (544 repeats), 2) intermediate (4554 repeats), 3) premutation (55200 repeats), and 4) full mutation (greater than 200 repeats) 17 18 Table 5.

A person with 55200 repeats does not have features associated with fragile X syndrome but is at increased risk of fragile X-associated tremor/ataxia syndrome (also known as FXTAS) and FMR1-related premature ovarian failure. When more than 200 repeats are present, an individual has a full mutation that results in the full expression of fragile X syndrome in males and variable expression in females. The large number of repeats in a full mutation allele causes the FMR1 gene to become methylated and inactivated.

Transmission of a disease-producing mutation to a fetus depends on the sex of the parent transmitting the mutation and the number of cytosineguanineguanine repeats present in the parental gene. Repeats very rarely expand during spermatogenesis in the male, such that only an affected male can transmit the full mutation to his female offspring. However, repeats in the female may expand during oogenesis, such that women with the premutation may transmit a full mutation, which results in an affected child. The larger the size of the premutation repeat, the more likely that there will be expansion to a full mutation Table 5. Women with an intermediate number of triplet repeats (4554) do not transmit a full mutation to their male and female offspring, although there may be expansion to a premutation allele in their offspring. Diagnosis of mutation size may vary by as many as 3 or 4 repeats. The frequency of premutation allele carriers (repeat size greater than 54) in the population has been reported to be as high as 1 in 157 in a large Israeli study of women (more than 36,000 individuals) without a family history of intellectual disability or developmental abnormalities 19. The most recent prevalence data from the United States reported a carrier frequency of 1 in 86 for those with a family history of intellectual disability and 1 in 257 for women with no known risk factors for fragile X syndrome 20.

Fragile X premutation carrier screening is recommended for women with a family history of fragile X-related disorders or intellectual disability suggestive of fragile X syndrome and who are considering pregnancy or are currently pregnant. If a woman has unexplained ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40 years, fragile X carrier screening is recommended to determine whether she has an FMR1 premutation. Although following these guidelines will not detect most premutation carriers in the population, the guidelines do target a higher prevalence group based on current data with regard to carrier frequency. If a patient with no family history requests fragile X screening, it is reasonable to offer screening after informed consent. All identified individuals with intermediate results and carriers of a fragile X premutation or full mutation should be provided follow-up genetic counseling to discuss the risk to their offspring of inheriting an expanded full-mutation fragile X allele and to discuss fragile X-associated disorders (premature ovarian insufficiency and fragile X tremor/ataxia syndrome).

Prenatal diagnostic testing for fragile X syndrome should be offered to known carriers of the fragile X premutation or full mutation. Fetal DNA analysis from amniocentesis or chorionic villus sampling reliably determines the number of triplet repeats. However, there are caveats in interpretation of chorionic villus sampling results: in some cases, an analysis of FMR1 gene methylation in full mutations from samples of chorionic villi may not be accurate, and a follow-up amniocentesis is necessary to accurately determine the methylation status of the gene 21. These limitations should be discussed with an obstetriciangynecologist or other health care provider with the requisite genetics expertise before ordering any testing. DNA-based molecular analysis (eg, Southern blot analysis and polymerase chain reaction) is the preferred method of diagnosis of fragile X syndrome and of determining FMR1 triplet repeat number (eg, premutations). In rare cases, the size of the triplet repeat and the methylation status do not correlate, which makes it difficult to predict the clinical phenotype. In cases of this discordance, the patient should be referred to a genetics professional.

A number of clinically significant, autosomal recessive disease conditions are more prevalent in individuals of Ashkenazi Jewish (Eastern European and Central European) descent. Most individuals of Jewish ancestry in North America are descended from Ashkenazi Jewish communities and, thus, are at increased risk of having offspring with one of these conditions. When only one partner is of Ashkenazi Jewish descent, that individual should be offered screening first. If it is determined that this individual is a carrier, the other partner should be offered screening. However, the couple should be informed that the carrier frequency and the detection rate in non-Jewish individuals are unknown for most of these disorders, except for TaySachs disease and cystic fibrosis. Therefore, it is difficult to accurately predict the couples risk of having a child with the disorder.

The American College of Obstetricians and Gynecologists has previously recommended offering carrier screening for four conditions in the Ashkenazi population:

Canavan disease is a severe degenerative neurologic disease. The phenotype is quite variable, but patients typically present in the first few months of life with delayed motor milestones (eg, head control and sitting). They will manifest macrocephaly, hypotonia, and intellectual disability. Life expectancy is variable, but many individuals die in childhood or adolescence. Treatment is primarily supportive because there is no cure. The disease is caused by mutations in the gene for aspartoacylase, which is involved in the metabolism of N-acetyl-L aspartic acid.

Cystic fibrosis is discussed elsewhere in this document.

Familial dysautonomia, a disorder of the sensory and autonomic nervous system, is associated with significant morbidity. Clinical features include abnormal suck and feeding difficulties, episodic vomiting, abnormal sweating, pain and temperature insensitivity, labile blood pressure levels, absent tearing, and scoliosis. Treatment is available that can improve the length and quality of life, but there currently is no cure. In 2001, the gene for familial dysautonomia was identified. At least two mutations in the familial dysautonomia gene, IKBKAP, have been identified in patients of Ashkenazi Jewish descent with familial dysautonomia. One of the mutations, IVS20(+6T->C), is found in more than 99% of patients with familial dysautonomia. It occurs almost exclusively in individuals of Ashkenazi Jewish descent; the carrier rate (1 in 32) is similar to TaySachs disease and cystic fibrosis 22.

TaySachs disease is discussed elsewhere in this document.

Some experts have advocated for a more comprehensive screening panel for those of Ashkenazi descent, including tests for several diseases that are less common (carrier rates 1 in 15 to 1 in 168). The following is a list of autosomal recessive conditions for which screening should be considered in individuals of Ashkenazi descent:

Bloom syndrome is characterized by short stature, skin rash with sun exposure, and increased risk of cancer of any type. Affected individuals often have a high-pitched voice, distinctive facial features, learning disabilities, increased risk of diabetes, and chronic obstructive pulmonary disease. It is caused by mutations in the BLM gene, which codes for a protein family known as the RecQ helicases.

Familial hyperinsulinism is a condition in which the pancreas produces too much insulin, which results in low blood sugar caused by mutations in the ABCC8 gene.

Fanconi anemia can be caused by mutations in at least 15 different genes, but 8090% of cases are due to mutation in one of three genes: 1) FANCA, 2) FANCC, and 3) FANCG. Affected individuals can experience bone marrow failure; increased risk of cancer, including leukemia and solid tumors; and structural defects such as short stature, skin pigment changes, nervous system abnormalities (including central nervous system malformations), eye and ear malformations and hearing loss, skeletal abnormalities in particular affecting the thumb or forearms, gastrointestinal abnormalities (including effects on the oral cavity), and others. Of note, 2540% of affected individuals do not have any physical abnormalities 23.

Gaucher disease is caused by mutations in the GBA gene, which codes for the enzyme beta-glucocerebrosidase; this enzyme is responsible for the metabolism of glucocerebroside into glucose and ceramide. There are multiple types. Type 1 is the most common and does not affect the central nervous system. The symptoms can range from mild to severe and may not present until adulthood. Individuals present with hepatosplenomegaly, anemia, thrombocytopenia, lung disease, and bone abnormalities. Type 2 and type 3 Gaucher disease cause the aforementioned symptoms and signs and affect the central nervous system, including abnormal eye movement, seizures, and brain damage. Individuals with Type 2 can experience life-threatening issues early in life. There is also a perinatal lethal form, which can cause complications that manifest before birth or early in infancy. Finally, there is a cardiovascular type, which is characterized by calcification of the cardiac valves.

Glycogen storage disease type I (also known as von Gierke disease) is caused by the buildup of glycogen in body cells, particularly the liver, kidneys, and small intestine, and leads to malfunction of these organs. The signs and symptoms present early in life, approximately age 34 months.

Joubert syndrome is caused by mutations in genes related to the structure and function of cilia. Manifestations include the molar tooth sign on magnetic resonance imaging of the brain, which indicates abnormal development of the brainstem and cerebellar vermis; infants also can have hypotonia and ataxia, unusually fast or slow breathing, intellectual disability, and developmental delays.

Maple syrup urine disease is caused by mutations in the BCKDHA, BCKDHB, and DBT genes, which encode proteins that are essential for breaking down the amino acids leucine, isoleucine, and valine. The urine of affected infants has a distinctive sweet odor. Affected individuals manifest poor feeding, lethargy, and developmental delays. Without treatment, this condition can be lethal.

Mucolipidosis type IV is caused by mutations in the MCOLN1 gene, which is involved in the function of lysosomes; dysfunction of this gene leads to accumulation of lipids and proteins in lysosomes. Affected individuals have severe psychomotor delays and visual impairment.

NiemannPick disease can present in a variety of ways, with affected individuals exhibiting a range of severity. There are four main types: 1) A, 2) B, 3) C1, and 4) C2. Those with type A have a cherry-red spot in the eye; they often have failure to thrive, and at approximately age 1 year begin to exhibit psychomotor regression and widespread lung damage. Most do not survive beyond early childhood. Type A is the most common form in the Jewish population. Types B, C1, and C2 are not as severe as type A and present later in childhood, although all three can manifest with lung disease. Individuals with types C1 and C2 develop neurologic compromise that eventually interferes with feeding ability and intellectual function.

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Carrier Screening for Genetic Conditions | ACOG