Category Archives: Genetics

NEW YORK Foundation Medicine and Flatiron Health announced this week that Foundations comprehensive genomic profiling tests will be available to order through Flatiron's OncoEMR platform. The integration will allow clinicians to electronically order, track, and receive Foundations test through OncoEMR, the companies said. Both Flatiron and Foundation are planning further integrations with the others comprehensive genomic profiling tests and electronic medical record systems, respectively.

Myriad Genetics this week said it has completed the sale of its Myriad RBM unit which specializes in providing laboratory research services to pharmaceutical companies to IQVIA subsidiary Q2 Solutions. When Myriad announced its intent to sell this business unit in May, it did not disclose the deal's financial details.

GenetronHealth said this week that it has entered a new partnership with the World Economic Forum under its Health and Healthcare Platform, where it is contributing its research insights, technologies, and industry experience. The platform's overall goal is to ensure worldwide equal access to the highest standards of health and healthcare.Genetroniscurrentlyparticipating in a sub-project,dubbedMoving Genomics to the Clinic, which seeks to promote the use of genetic testing in routine clinical practices by proving its utility and efficacy.

AccessHope, a City of Hope subsidiary, said this week that it has partnered with the Dana-Farber Cancer Institute to bring the latest cancer care expertise to patients and oncologists in the community. By partnering withAccessHope, Dana-Farber's experts will support oncologistswiththe latest advances in oncology,includingpersonalized treatments, clinical trials, promising investigational medications, and molecular testing. Patients in Massachusetts, Maine, New Hampshire, Vermont, Connecticut, Rhode Island, New York,and New Jersey, as well asthosein other parts of the country,can access these services through their employee benefits programs. City of Hope and Northwestern University's Robert H. Lurie Comprehensive Cancer Center are also foundational members ofAccessHope.

Molecular breath analysis startup Deep Breath Intelligencesaid this week that it has entered a collaboration with Lwenstein Medical, a sleep and respiratory medicine firm based inRheinland-Pfalz, Germany.Rotkreuz, Switzerland-based DBI said that it is applying artificial intelligence to identify breath biomarkers related to obstructive sleep apnea syndrome. DBIsaid ithas initiated a study on OSASin collaboration with Lwenstein Medical,using participantsbreath samples and applying DBIs patterned analytical algorithms to provide results.

Enable Biosciences said this week it is partnering with the California Department of Public Health to survey state residents for the presence of antibodies against SARS-CoV-2. As part of the program, more than 200,000 households in California will be invited to submit dried blood samples collected at home using kits developed by Enable Bio andtheCDPH. The samples will then be tested by Enable Bio for the presence of antibodies against SARS-CoV-2 to distinguish antibody response fromviralinfection versusresponse fromvaccination. Test results will provide information about the spread of COVID-19 in California and the uptake of vaccines for the disease, South San Francisco, California-based Enable Bio said. The project is a collaboration betweenthe company,theCDPH, Stanford University, and Gauss Surgical. The first survey period concluded June 15 with the second and third enrollment periods slated tobeginat the start of 2022.

NeoGensaid this week that it has extended itsglobalanimal genomicspartnership withGencove. Thepartnership allowsNeoGento offerGencove'sSkimSeeklow-pass sequencing technology to customers in the agricultural sector, including those in the bovine, canine,poultry, and swine industries. UsingGencove'ssequencingimputationplatform,NeoGensaid it can deliver increased genomics data with improved accuracy and flexibility.

Bioceptsaid this week ithas been added to the Russell Microcap Index. Michael Nall, Biocept's president and CEO,called the nodexceptionally exciting, as a driver ofawarenessfor the cancer liquid biopsy firm within thelargerglobal investment community.

Immunoviasaid this week that its American subsidiary hasreceived a CLIA Certificate of Registration,which isan important step in the accreditation of its laboratory in Marlborough, Massachusetts, and a prerequisite to receiving clinical laboratory licensure fromtheMassachusetts Department of Public Health. Clinical laboratory licensure is required beforeImmunoviacan begin testing patients with itsImmrayPanCan-d test, the firm said.According to the Centers for Medicare and Medicaid Services, a Certificate of Registration allows a laboratory toconduct moderate and/or high complexity testing until it is inspected to determine its compliance with the CLIA regulations.

In Brief This Week is a selection of news items that may be of interest to our readers but had not previously appeared onGenomeWeb.

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In Brief This Week: Foundation Medicine, Myriad Genetics, Genetron Health, and More - GenomeWeb

Arabidopsis plants were used to develop the first CRISPR-Cas9-based gene drive in plants. Credit: Zhao Lab, UC San Diego

New technology designed to breed more robust crops to improve agricultural yield and resist the effects of climate change.

With a goal of breeding resilient crops that are better able to withstand drought and disease, University of California San Diego scientists have developed the first CRISPR-Cas9-based gene drive in plants.

While gene drive technology has been developed in insects to help stop the spread of vector-borne diseases such as malaria, researchers in Professor Yunde Zhaos lab, along with colleagues at the Salk Institute for Biological Studies, demonstrated the successful design of a CRISPR-Cas9-based gene drive that cuts and copies genetic elements inArabidopsisplants.

Breaking from the traditional inheritance rules that dictate that offspring acquire genetic materials equally from each parent (Mendelian genetics), the new research uses CRISPR-Cas9 editing to transmit specific, targeted traits from a single parent in subsequent generations. Such genetic engineering could be used in agriculture to help plants defend against diseases to grow more productive crops. The technology also could help fortify plants against the impacts of climate change such as increased drought conditions in a warming world.

A schematic representation of a new plant gene drive using CRISPR/Cas9 technology. Credit: Zhao Lab, UC San Diego

The research, led by postdoctoral scholar Tao Zhang and graduate student Michael Mudgett in Zhaos lab, ispublished in the journalNature Communications.

This work defies the genetic constraints of sexual reproduction that an offspring inherits 50% of their genetic materials from each parent, said Zhao, a member of the Division of Biological Sciences Section of Cell and Developmental Biology. This work enables inheritance of both copies of the desired genes from only a single parent.The findings can greatly reduce the generations needed for plant breeding.

The study is the latest development by researchers in theTata Institute for Genetics and Society(TIGS) at UC San Diego, which was built upon the foundation of anew technology called active genetics with potential to influence population inheritance in a variety of applications.

Developing superior crops through traditional genetic inheritance can be expensive and time-consuming as genes are passed through multiple generations. Using the new active genetics technology based on CRISPR-Cas9, such genetic bias can be achieved much more quickly, the researchers say.

I am delighted that this gene drive success, now achieved by scientists affiliated with TIGS in plants, extends the generality of this work previously demonstrated at UC San Diego, to be applicable in insects and mammals, said TIGS Global Director Suresh Subramani. This advance will revolutionize plant and crop breeding and help address the global food security problem.

Reference: Selective inheritance of target genes from only one parent of sexually reproduced F1 progeny in Arabidopsis by Tao Zhang, Michael Mudgett, Ratnala Rambabu, Bradley Abramson, Xinhua Dai, Todd P. Michael and Yunde Zhao, 22 June 2021, Nature Communications.DOI: 10.1038/s41467-021-24195-5

Coauthors of the paper include: Tao Zhang, Michael Mudgett, Ratnala Rambabu, Bradley Abramson, Xinhua Dai, Todd Michael and Yunde Zhao.

The research was funded by TIGS-UC San Diego and a training grant from the National Institutes of Health.

Original post:
New CRISPR/Cas9 Plant Genetics Technology to Improve Agricultural Yield and Resist the Effects of Climate Change - SciTechDaily

Research has shown that changes in certain genes can increase a persons risk of developing Alzheimers disease (AD). The strongest known genetic risk factor for AD is a form of the apolipoprotein E (APOE) gene called APOE 4. APOE helps carry cholesterol and other fats in the bloodstream, and problems in this process are thought to contribute to AD. NIA-supported researchers recently found that the level of APOE in the brain is dependent on the individuals genetic ancestry surrounding the APOE gene. Led by a team at the University of Miami, these study results were published in Alzheimers & Dementia on Feb. 1.

Everyone inherits two copies of the APOE gene, one from each biological parent. There are three forms, or variants, of APOE that have been shown to alter risk for AD: APOE 2, APOE 3, and APOE 4. On average, people of European ancestry who inherit two copies of APOE 4 have about 10 times the risk of AD compared with people who have only the other two variants. Interestingly, researchers have known for some time that carriers of APOE 4 in African ancestry populations, such as Africans and African Americans, have a lower risk for developing AD than European carriers, while carriers of APOE 4 from Asia have a much higher risk for AD from APOE 4 than Europeans. Earlier studies by the University of Miami researchers in individuals who had both European and African ancestries found that it was the genetic ancestry surrounding the APOE gene that determined the risk, not the gene itself. That is, if a person inherited their APOE 4 gene from their African ancestor, they had the African risk for AD; if they inherited it from their European ancestor, they had the European risk for AD. In the new study, researchers wanted to find out how the same gene variant can cause different levels of risk based on genetic ancestry.

The researchers tested whether genetic ancestry affects the expression of the APOE gene in the brain. They used a technique called single-nucleus RNA sequencing to measure how many APOE transcripts, or RNA copies of the gene, were in each individual cell in the brain. Because a genes transcripts have the instructions to make protein, this measurement gives an estimate of how much APOE protein is being produced in these cells. The researchers tested autopsy brain tissue samples from AD patients: four patients of African ancestry who had inherited APOE 4 from African ancestors and seven non-Hispanic white patients who had inherited APOE 4 from their European ancestors.

On average, the researchers found that cells in the brains of patients with European genetic ancestry surrounding APOE 4 had almost 40% more APOE transcripts than the samples from individuals who had African genetic ancestry surrounding APOE 4. Samples from the European genetic ancestry surrounding APOE 4 also had more of a type of brain cell called A1 reactive astrocytes, which are thought to be involved in the cellular degeneration process of AD. These reactive astrocytes produced the highest levels of APOE 4 expression compared to other cell types. The researchers hypothesize that the region of DNA surrounding APOE 4, which differs between people with European ancestry and people with African ancestry, has important information, such as regulatory elements, that controls how much APOE is produced.

The authors note that they had a small sample size because autopsy brain samples from individuals of African ancestry with AD are scarce. They emphasize that to advance the field of Alzheimers research, it is important to encourage people from all ancestral backgrounds to participate in clinical and genetic research, including tissue donation. The studys results could help researchers develop ways to block APOE 4 activity to reduce the risk of AD in people who have this gene variant.

This research was supported in part by NIA grants R01-AG059018, U01-AG052410, RF1-AG054074, U01-AG057659, P50-AG0256878, and P30-AG013854.

These activities relate to NIHs AD+ADRD Research Implementation Milestone 2.G, Maximize the translational potential of genetics research by ensuring rapid and broad sharing of large-scale genetic/genomic data.

Reference: Griswold AJ, et al. Increased APOE 4 expression is associated with the difference in Alzheimers disease risk from diverse ancestral backgrounds. Alzheimers & Dementia. 2021. ePub Feb 1. doi: 10.1002/alz.12287.

Read more from the original source:
Study finds differences in APOE 4 expression based on genetic ancestry - National Institute on Aging

Jul 01, 2021 5:30 PM

Author: Doug Dollemore

During his 17-year career with the New York Yankees, Lou Gehrig was famed for his prowess as a hitter and for his durability on the baseball field, which earned him his nickname "The Iron Horse. Then, mysteriously, in 1938, his iron body began to figuratively rust. He couldnt run, hit, or field his position as well as he once did. When doctors finally diagnosed his condition, the news was devastating.

Gehrig had amyotrophic lateral sclerosis (ALS), a rare progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. People who have ALS gradually lose their ability to control muscle movement. Eventually, the condition, now often referred to as Lou Gehrigs disease, leads to total paralysis and death. Then, as now, there is no cure.

In the 80 years since Gehrigs death at age 37, scientists have sought to unravel what causes the disease and develop better treatments for it.

In the latest advance, University of Utah Health researchers have detected a set of genetic mutations that appear to increase a persons risk of developing ALS. They say the discovery of mutations in TP73, a gene that has never been associated with ALS before, could help scientists develop new therapies to slow or even stop the progression of the disease.

Its really a novel discovery that suggests a very different pathway for the onset of at least some cases of ALS that hasnt been explored before, says Lynn Jorde, Ph.D., chair of the Department of Human Genetics at U of U Health and the senior author of the study. From a scientific standpoint, its going to provide us with a more complete picture of what is going wrong in ALS and expand our understanding of what can be done to mitigate its devastating consequences.

The study appears in Neurology, the medical journal of the American Academy of Neurology.

"From a scientific standpoint, its going to provide us with a more complete picture of what is going wrong in ALS and expand our understanding of what can be done to mitigate its devastating consequences."

About 85% of ALS cases are sporadic, meaning that no one in a patients family has a history of the disease. However, researchers suspect that up to 61% of sporadic ALS cases are influenced by genetic factors. But detecting those factors has been challenging.

In the past, it has been difficult to determine ALS-causing genes because only recently has sequencing technology advanced enough to feasibly sequence many patients, says Kristi L. Russell, a graduate research assistant at U of U Health and lead author of the study. Additionally, many mutations in a single patient could be considered deleterious, so one must test the candidate mutations in animal models or cell culture, an incredibly time-consuming process.

For this study, Jorde, Russell, and colleagues analyzed blood samples provided by 87 people with sporadic ALS who were being treated at U of U Health. Using a technique called exome sequencing, which zeroes in on the protein-coding regions within genes, they found five people who had rare, deleterious mutations in the TP73 gene, which plays a key role in apoptosis or programmed cell death. Then, the researchers studied data from 2,900 other sporadic ALS patients from the Utah Heritage 1K Project and the ALSdb cohort. Within these groups, they identified 24 different, rare protein-coding variants in TP73.

When the researchers did a similar analysis among 324 people who did not have ALS, the patient mutations in TP73 were not present.

In subsequent laboratory studies, knocking out or disabling TP73 in zebrafish impaired the development of nerve cells in a way that mimicked what appears to occur in ALS. Like in ALS, the zebrafish had fewer motor neurons and shorter axons, nerve fibers that transmit electrical impulses from neurons to muscle cells. This shortening could impede the axons ability to transmit impulses. Shorter axons transmit these impulses far less efficiently.

During their experiments, the researchers also found evidence that mutant TP73, which normally inhibits apoptosis in motor neurons, doesnt work properly. As a result, they suspect that apoptosis is more likely to occur.

It seems that mutant TP73 disrupts apoptosis, which leads to more neuronal death, Russell says. Many biological pathways have been implicated in ALS progression, but our study highlights the underappreciated role of apoptosis in ALS pathology. Apoptosis could potentially become a new focus or target for treatment drug screens.

More here:
Newly Discovered Genetic Mutations May Increase Risk for Lou Gehrig's Disease - University of Utah Health Sciences

Introduction

Fragile X syndrome (FXS), OMIM # 300624, is a X-linked inherited genetic disease classified as a triplet repeat condition. FXS is the most common cause of inherited intellectual disability and autism in the world. It has a prevalence of 1 in 5000 men and 1 in 8000 women. Affected individuals are characterized by intellectual disability, autism, language deficit, typical facies, and macroorchidism.1,2

Alterations in the FMR1 gene with locus Xq27.3 are causative of Fragile X Syndrome and other disorders. This gene harbors a CGG repeat within the 5 untranslated region and, depending on the number of repetitions, 4 types of alleles are defined with different clinical manifestations:3 Normal alleles, which have up to 44 CGG repeats; grey zone or intermediate alleles that contain between 45 and 54 repeats; premutation (PM) alleles with between 55 and 200 repeats; and full mutation (FM) alleles, with more than 200 repeats. In most cases, this is due to an expansion of the CGG triplet from one generation to the next.4

The Fragile Mental Retardation Protein (FMRP) is coded by the FMR1 gene. The absence of FMRP expression is usually secondary to the methylation of the FMR1 gene that occurs when more than 200 CGG repeats are present in the 5UTR region; this can also be explained by a point mutation in the coding region for FMR1 or a deletion that includes this gene, but these changes have only been reported in a few cases. The absence of FMRP is related to the classic FXS phenotype.5,6

FMRP expression is slightly lower in the carriers of a PM allele. Lower levels of FMRP are found particularly in the upper premutation (PM) range however, they typically do not present the classic FXS syndrome phenotype.7 Furthermore, they have elevated FMR1 mRNA levels between 2 to 8 times normal levels, which also leads to RNA toxicity. These elevated levels of mRNA are a risk for a number of medical conditions that are not explained by decreased FMRP.2,4,8

FMRP has roles in chromatin dynamics, RNA binding, mRNA transport, and mRNA translation9,10 and for certain subgroups of cerebral transcripts.11

This protein is involved in the regulation of RNA stability, subcellular transport and translation of neural mRNAs that codify proteins involved in synapsis development, neural plasticity and brain development.8

In addition, FMRP interacts with at least 180 proteins expressed in the brain and connective tissue. This interactome comprises known FMRP-binding proteins, including the ribosomal proteins FXR1P, NUFIP2, Caprin-1, and other novel FMRP-interacting candidate proteins located in different subcellular compartments, including CARF, LARP1, LEO1, NOG2, G3BP1, NONO, NPM1, SKIP, SND1, SQSTM1 and TRIM28. This interactome suggests that, besides its known functions, FMRP is involved in transcription, RNA metabolism, ribonucleoprotein stress granule formation, translation, DNA damage response, chromatin dynamics, cell cycle regulation, ribosome biogenesis, miRNA biogenesis and mitochondrial organization.9

Several studies have shown that in the absence of FMRP, a wide range of neural mRNAs are affected, boosting neural protein synthesis, which results in dendritic spine dysmorphogenesis and glutamate/GABA imbalance, which in turn produce variations in neural excitation/inhibition, phenomena that are present in FXS. Dendritic spine dysmorphogenesis plays a role in the intellectual deficits and behavioral problems, due to the weak synaptic connections found in this syndrome.12,13

Fragile X syndrome (FXS) has incomplete penetrance and variable expressivity and biological sex is a decisive factor of the phenotype. Full mutation of the FMR1 gene has a 100% penetrance of intellectual disability in males and 60% in females. Other characteristics associated with FXS Appear with varying frequencies in affected individuals. Autism spectrum disorder (ASD) symptoms appear during early childhood in 50% to 60% of males and 20% of females with FXS.1417

Physical features include elongated face, large and prominent ears (7578% of affected males), mandibular prognathism (80% of adult men), hyperlaxity and macroorchidism (95% of adult men). Other characteristics also vary in their frequency of presentation: seizures (23%), strabismus (8%), and cardiac abnormalities such as abnormal aortic root dimensions (18%) and mitral valve prolapse (55%). In general, the female phenotype is less severe and less specific.4,18

The variation in the phenotype of monogenic diseases is common,19,20 it is explained by a combination of genetic, environmental, and lifestyle factors,21 and FXS is not an exception.

Here, we present a review of the knowledge about the molecular factors involved in the variable expressivity of FXS.

The presence of a full mutation in FMR1 is associated with the hypermethylation of a CpG island located in the promoter of the FMR1 gene. Methylation of DNA regions (mDNA) is one of the main epigenetic modifications related to transcription regulation.22 A CpG island is located proximal to the CGG repeat tract, which is expanded in FXS. Hypermethylation of the CpG island generates transcriptional silencing of the FMR1 gene.23 As a consequence, the Fragile Mental Retardation Protein (FMRP), codified by the FMR1 gene, is not produced24 and in turn, the absence or low expression of FMRP causes FXS.

CGG tract repetition expansion in the untranslated region (UTR) of exon 1 in the FMR1 gene generates instability of that region during the replication process, inducing size mosaicism, which is defined as the presence of premutation and mutation alleles in several cells.25

In males with FXS caused by full mutation, the detection of FMR1 mRNA levels in peripheral blood lymphocytes is common. This phenomenon is due to both size mosaicism and mDNA in the CpG island and nearby regions that vary between cells and tissues.26 Furthermore, longitudinal studies in women with FXS have shown that levels of mRNA transcribed from FMR1 decrease significantly with age.23 Complicating even more the behavior of mDNA and FXS, it has been found that in premutation alleles, a considerable number of cells have mDNA.27 The variation between methylation states of the CpG island and nearby regions among different cells and tissue of the same person is known as methylation mosaicism.28 It is estimated that around 50% of people with FXS have this type of mosaicism.29 In cells where mutated alleles are not methylated, they are transcriptionally active and can be expressed.30 However, in these cells there is no FMRP synthesis since mRNA with CGG expansion greater than 200 repeats is not translated efficiently in ribosomes.31,32

The absence or low levels of FMRP is a decisive factor for FXS development, as several studies have aimed to discover the relationship between protein levels and phenotypic characteristics of the patients. Since the late 1990s, correlations between FMRP levels and the neurological phenotype of FXS have been established.29,33,34 The first studies about this topic established the standard levels of FMRP in peripheral blood leucocytes through immunoblotting. When comparing protein levels with the allele type and the presence of size mosaicism, it was demonstrated that people with the lowest FMRP levels were males with FM. Males with size mosaicism and females with FM had slightly higher levels of FMRP than males with FM.33,35,36 Via multiple regression models, it was found that FMRP levels were significantly correlated with the intelligence quotient (IQ) of the patients in the study.33 However, studies did not identify the same relation between FMRP levels and behavioral symptoms.34,37 More recent evidence supports a partial overlap between the pathogenic mechanisms that lead to FXS and ASD.38 Lower FMRP levels have been documented in samples of individuals with FXS and ASD compared to patients with FXS only.29,34 The relation between FMRP levels and IQ in males and females with different expansions in CGG repeats was studied recently.39 This last study has two important advantages compared with previous studies: firstly, the use of fluorescence resonance energy transfer (FRET), which has a higher sensibility when measuring protein levels, and also FMRP levels were measured in dermal fibroblasts. Unlike leucocytes, fibroblasts derive from the ectoderm, the same germ layer from which nervous system cells originate. Researchers found a strong and positive relation between FMRP levels and cognitive skills in patients with levels below 30% of the standard levels in controls. Interestingly, above this level, there was a higher dependence between low FMRP levels and low IQ.39

In parallel with the aforementioned studies, researchers reported the incidence of size and methylation mosaicism in cognitive impairment severity.4042 The classic definition of premutation alleles behavior as non-methylated alleles, and mutated alleles as methylated or partially methylated ones in order to categorize premutation carriers and patients with FXS has been extended progressively to include a detailed classification that takes into account the existence of size and methylation mosaicisms.

Regarding size mosaicisms, different combinations have been described, including patients with some FM cells and other cells with PM. Indeed, patients with FM, PM, grey zone alleles and even alleles with normal size have been reported.40 The presence of size mosaicisms with PM and FM alleles is related with a less severe phenotype and a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS).43

When exploring the possible relation between size mosaicisms and the intellectual functioning of patients with FXS disregarding sex, it was found that patients with FM/PM had better intellectual functioning and less maladaptive behavior, compared with FM-affected individuals.42 Interestingly, the same study found that ASD features and maladaptive behaviors were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. A limitation of this study is that they used venous blood and real time PCR and Southern blot analysis to quantify the level of methylation.

Recently, methylation mosaicism has been taken into account as an important variable in phenotype traits. The most frequent mosaicism found in males is the presence of FM-methylated alleles and non-methylated FM and PM alleles (combination of size and methylation mosaicism).25,44 However, in patients with FM and not PM mosaicisms, methylated alleles do not express mRNA, while non-methylated alleles do. An aspect that highlights the importance of detecting the presence of this kind of mosaicism is the influence on phenotype severity. Additionally, according to some case reports, the presence of synthesized mRNA from PM and FM alleles increases the odds of developing the FXTAS phenotype.45,46 The final consequence of methylation mosaicism is the cells reduced ability to express FMR1 mRNA, measure mRNA and determine if there is a relation with phenotypic traits. When analyzing mRNA levels between males and females, it was found that females had higher levels. Also, in females, higher levels of FMR1 mRNA were related positively with age but not with intellectual functioning and autistic features. Males with FM that express FMR1 mRNA had significantly higher ADOS calibrated severity scores, when compared with males with fully methylated FM. Interestingly, no differences were found regarding intellectual functioning.41 Likewise, when contrasting FMR1 mRNA levels and scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-CfX) it was found that in males with FM, higher values of FMR1 mRNA were related with elevated irritability and lower health-related quality of life scores.47 This association was not found in males with PM/FM, suggesting that for improved genotype/phenotype associations, it is essential to take into consideration not only sex but also size and methylation mosaicism.

Recent investigations explored simultaneously how FMR1 mRNA levels of FMRP are related to phenotypic alterations in males with PM and FM.48 In a study composed of 14 cases of patients with PM or PM and FM mosaicism and mental illnesses such as bipolar disorder, schizophrenia and psychosis, among others, low levels of FMRP and increased FMR1 mRNA were evident in these patients. This combination of characteristics in patients with FM, decreased FMRP, PM and increased FMR1 mRNA represents a dual mechanism of clinical significance that may generate characteristics of both FXS and FXTAS.48 In a clinic-based ascertained group of patients with FXS of both gender, a significant difference was found between FXS with ASD and low levels of FMRP when comparing concentrations of the protein in patients with FXS without ASD.29 They found that the mean full scale IQ and adaptive skills composite scores were significantly lower in males than in females (p = 0.016 and p = 0.001, respectively, MannWhitney). Additionally, all individuals with moderate or severe ID were males. Not surprisingly, ASD was present more frequently in males with FXS (46% vs 20% females). This association was not found in males with PM/FM, suggesting that for improved genotype/phenotype associations is essential to take into consideration not only sex but size and methylation mosaicism.29

There is a small proportion of FXS patients without expansions in the CGG-repeat tract. In this group, the condition is caused by missense or nonsense mutations,5,16 or deletions in FMR1.1,6 Patients with these mutations have similar physical, cognitive and behavioral characteristics to FXS patients. With the increasing availability of diagnostic methods based on next-generation sequencing and comparative genomic hybridization, a higher rate of diagnosis of mutations causing FMR1 function loss is expected. This will allow a clear delimitation of the phenotype caused by the loss of the protein in the absence of CGG tract expansions.

For many monogenic diseases it is known that, besides the allelic variance, the effect of modifier genes has an important role in incomplete penetrance and variable expressivity. The identification of modifier genes that affect the phenotype in monogenic diseases has many challenges that complicate their description. A genetic variant can modify the effect in the phenotype of another variant in many ways, including epistasis and genetic interactions.49,50

In studies using FXS murine models, important new evidence was acquired in order to establish the importance of potential modifier genes and their impact on FXS phenotype development. The knockout mouse model for FXS was generated in the last decade of the XX century. Fmr1 KO mice had learning deficits, abnormal synaptic connections, seizures, hyperactivity and macroorchidism.51,52 When describing the mouse phenotype in detail, it was evident that abnormal phenotypic characteristics depend, at least in some proportion, on their genetic background.53

During the identification of modifier genes in the FXS phenotype, a large proportion of the research has aimed towards the susceptibility to developing certain clinical behavioral characteristics, such as aggression, ASD and seizures.34,5459 All of the studies use a similar methodological design: they arrange groups of people with or without a specific phenotypic trait and establish the frequency of specific variants in modifier gene candidates.

The possibility that Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype in FXS patients has also been investigated. The replacement of a methionine for a valine in the 66th position of the BDNF protein interferes with normal intracellular traffic and BDNF dependent secretory activity in cortical neurons.60 This polymorphism has been related to cerebral anatomy alterations61 and neuropsychiatric disorders.62,63 In a sample of 27 males with FXS from Finland, it was found that all the patients with epilepsy (15%) had the Met66 allele, whereas the prevalence of this allele is 20% in the normal population. Research suggests that the Met66 allele in BDNF interacting with FM in FMR1 may partially explain the higher incidence of seizures in patients with FXS.56 In a more recent study with a higher number of males with FXS (77 patients), the results were not replicated and there was no association between seizures and Val66Met polymorphism.58 These results show the importance of validating studies about modifier genes in different populations.

In research about genes that affect mood and aggression, such as the serotonin transporter (5-HTTLPR), the monoamine oxidase A (MAOA-VNTR) and COMT, conflicting results were found. All of those genes are involved in regulatory pathways for different neurotransmitters, and their variants have been associated with the development of behavioral phenotypes in different contexts other than FXS. In one group of 50 males with FXS, the relationship of 5-HTTLPR and MAOA-VNTR polymorphisms with the frequency/severity of aggressive/destructive, self-injurious and stereotypic behaviors was studied. It was found that the high-transcribing long (L/L) genotype in 5-HTTLPR was related with a higher frequency of aggressive/destructive and stereotypic behavior, while patients with the short (S/S) genotype had less aggression. The MAOA-VNTR genotype had no effect on behavior.55 On the other hand, in a study of 64 males with FXS where the COMT gene was also included, the results of the previous study were not replicated. There was no association between behavioral characteristics and either 5-HTTL PR (serotonin) or MAOA genotypes. Nevertheless, the A/A genotype in COMT that modifies dopamine levels was associated with greater interest and pleasure in the environment, and with less risk of property destruction, stereotyped behavior and compulsive behavior.54 The authors of the study suggest that the non-reproducibility of the results regarding MAOA-VNTR can be explained by differences in the prevalence of aggressive and stereotyped behavior among the studied populations or by differences in the measurements used to characterize each behavior.

The importance of identifying potential modifier genes was explored in a clinical trial. The researchers investigated the relation between polymorphisms in several genes and the response of sertraline in 51 children. They found that BDNF, MAOA, 5-HTTLPR, Cytochrome P450 2C19 and 2D6 polymorphisms had significant correlations with treatment response.64

Currently the knowledge about molecular causes of the variable phenotype in patients with FXS include characteristics associated with the FMR1 gene itself and to secondary, modifying gene effects.

Regarding FMR1, when the diagnosis is established, the type of mutation causing FXS is identified: CGG repeat tract expansion vs pathological variant causing loss of function in FMR1.

When the CGG is identified, is it expected that about half of the patients have size or methylation mosaicism or both.29 The presence of any of those mosaicisms determines the expression or not of FMR1 mRNA and FMRP. The quantity of FMRP is directly related with IQ.34,37,39 While the presence of size mosaicism is related with better intellectual functioning and less maladaptive behavior,29,42 elevated concentrations of FMR1 mRNA in patients with FM have been associated with a higher risk of developing FXTAS45,46,48 and with the severity of behavioral symptoms.47

The search for modifier genes affecting the phenotype has been carried out using the candidate genes strategy. Because high impact clinical manifestations in FXS are related with neurologic phenotypes, the studied candidate genes are involved in CNS development and the appearance of seizures (BNDF)56,6062 and associated with mood and aggression (5-HTTLPR, MAOA-VNTR y COMT).54,55 Recent research has been done with small groups of patients and there are no conclusive results about the importance of these variants in modifier genes.

Scientific and clinical evidence about molecular causes of variable expressivity in FXS is growing quickly. It is evident that aspects of the mutation type in FMR1 and the behavior of the CGG repeat tract are relevant in the presentation of the condition. Research about modifier genes is still emerging. There are important limitations such as sample size and comparability of different studies, mainly due to smaller groups of selected patients and the use of different tools for measuring the phenotypes.

Independent cohorts of patients with FXS across different continents have shown evidence that mosaicism, FMR1 mRNA or FMRP quantification are associated with the severity of the phenotype. However, this information cannot currently be used effectively in the integral management of patients. When intervention strategies become available in order to prevent the development of FXTAS, or when certain molecules can regulate levels of FMRP expression to measure FMR1 mRNA and FMRP, they could be crucial for selecting patients and identifying the best therapeutic intervention.

In clinical trials there is an important window of opportunity. Identifying mosaicism, measuring transcription/translation activity of FMR1 and stratifying patients by modifier genotypes29,65 will permit the identification of subgroups of patients with greater potential to respond to specific treatments.

The authors report no conflicts of interest in this work.

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Genetic mapping of subsets of patients with fragile X syndro | TACG - Dove Medical Press

With so many great cannabis brands releasing exciting new products in new markets, it can be hard to keep track of every release. So we're rounding up a few significant releases. This week, we look at releases by Insane, Kal, and more.

Insane just came out with a new strain available at all Dr. Greenthumb dispensaries in California. Stuffed French Toast is a cross between Paris OG and Faceoff OG, and appeals to the wake 'n' bake crowd with a flavor profile of cinnamon, pine, and orange, tasting just like the breakfast staple it was named after.

Available: California

California-based topicals brand Papa & Barkley just announced infused THC capsules to its lineup. The two-ingredient, whole-plant THC Releaf Capsules are made from coconut and cannabis oils and contain 25 to 50 milligrams of THC.

Available: California

Compound Genetics started dropping three strains at the June 26 grand opening of the Cookies Santa Ana location. These strains include Apples and Bananas, Gummiez, dropping on July 1, and Pav, which was made in collaboration with rapper Quavo.

Available: California

Kal will be dropping new flavors on July 2 in its seltzer line in time for summer. Each 12-ounce can of Kal contains 15 milligrams of hemp-derived CBD and 2 grams of sugar. The new flavors include black cherry, ruby red grapefruit, ginger lemonade, and blood orange mango.

Available: Nationwide

High Tales, a video series produced by Monogram, the cannabis line from Jay-Z, just dropped its latest episode featuring rapper Curren$y. The episode shows Curren$y's very own grilled-cheese recipe, along with weed-related stories he's experienced throughout his life and career.

Available: Nationwide

Featured image by Gina Coleman/Weedmaps

Hannah is a Seattle-based writer and editor. Shes worked in the cannabis industry for three years and continues to learn and explore.

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4 new weed products to try from Compound Genetics, Papa & Barkley, and more - Weedmaps News

Inventum Genetics GmbH and Universitt Marburg agree on a collaboration

The project company of Xlife Sciences AG Inventum Genetics GmbH has signed a collaboration agreement with the Philipps-University of Marburg. In this way, Inventum Genetics has the exclusive opportunity to develop new therapeutic targets using high-quality genetic data.

ZUERICH, SWITZERLAND / ACCESSWIRE / June 22, 2021 / The cooperation between Inventum Genetics and the University of Marburg is a long-term agreement. In a first projects, new therapeutic targets and biomarkers for oncological, neurodegenerative and age-related diseases are be identified using the latest genetic and molecular biological processes. Oliver R. Baumann, CEO der Xlife Sciences, is delighted with the additional prospects for drug development: "All common diseases, like the majority of all oncological, neurodegenerative and age-associated diseases, are multifactorial in cause, not just caused by a singular genetic defect. Rather, multifactorial diseases are characterized by the fact that they are based on (exogenous) environmental factors and (endogenous) genetic risk factors. In this particular project with the University of Marburg, cellular disease mechanisms of multifactorial diseases are to be elucidated. For this purpose, cells are stimulated with exogenous risk factors. It will then be examined how the cells react to it depending on their genetic makeup."

The agreement with the Philipps-University of Marburg gives the university the right to pursue the results achieved in its own research and to industrialize them, provided Inventum Genetics does not use the results itself. In this case, Inventum Genetics would benefit from the royalties generated by the university.

About the Philipps-University Marburg The Institute for Human Genetics at the Faculty of Medicine at the Philipps-University of Marburg, under the leadership of Professor Dr. Johannes Schumacher is well recognized by high-ranking publications in research in the field of human genetics. The institute operates a molecular laboratory with high quality equipment and is therefore able to deal with complex issues in the context of molecular genetic research.

About Inventum Genetics GmbH Inventum Genetics GmbH is a subsidiary of Xlife Sciences AG, which is active in research, development, manufacturing and the sale of medical and biotechnological products, especially in the field of genetics. For more information, please visit: https://www.inventumgenetics.com

About Xlife Sciences AG Xlife Sciences AG is a Swiss company with focus on investing in promising technologies in the life science industry. Xlife Sciences AG is building the bridge from research and development to healthcare markets by supporting researchers and entrepreneurs in positioning, structuring, developing and implementing their concepts. Together with industrial partners or universities, Xlife Sciences AG leads projects through the proof-of-concept phase after an invention disclosure or start-up. Subsequently, the firm focuses on out-licensing or selling the company, often with a combination of a strategic partnership. Xlife Sciences AG offers its investors direct access to the further development of innovative and future-oriented technologies at a very early stage. For more information, please visit: http://www.xlifesciences.ch

For media inquiries:Dennis Lennartz, Head Investor Relations, Xlife Sciences AG, Tel. +41 44 385 84 60, dennis.lennartz@xlifesciences.ch

For scientific inquiries:Dr. Frank Plger, Chief Scientific Officer, Xlife Sciences AG, Tel. +41 44 385 84 62,frank.ploeger@xlifesciences.ch

SOURCE: Xlife Sciences AG

View source version on accesswire.com:https://www.accesswire.com/652623/Xlife-Sciences-AG-Collaboration-with-the-University-of-Marburg

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Xlife Sciences AG: Collaboration with the University of Marburg - BioSpace

MADRID, June 22, 2021 /PRNewswire/ -- We have recently witnessed, once again, a professional athlete suffering a cardiovascular attack during a match. This type of incidence and the possible fatal consequences result from an individual's genetic makeup. Genetic science now makes it possible to know whether a person has an elevated risk to suffer this type of cardiovascular accident and to avoid one of the main causes of death in the world, with more than 17 million deaths each year.

The role of genetics as a diagnostic element has been fundamental for several years, as Dr. Izquierdo, Chief Medical Officer of Veritas Intercontinental, says: "Sudden cardiac death (SCD) is mainly due to coronary pathologies, especially in patients over 40 years old, but in younger patients, such as many high-performance professional athletes, the contribution of genetic factors to the pathogenesis of SCD is a key factor, since we usually find a clear pattern of family inheritance at its origin, such as cardiomyopathies or channelopathies".

To help in the detection and prevention of Cardio Vascular Disease (CVD), Veritas Intercontinental offers the myCardiogenetic service, an innovative Exome sequencing and interpretation service, focused on genes related to hereditary heart diseases.

The analysis includes all genes recommended by the American Heart Association (AHA) analyzing 100 genes based on their relationship with different hereditary heart diseases. The service includes genetic counseling for the prescribing specialist, which is essential for the correct interpretation of the results and clinical management of the patient.

"myCardio,"explains Dr. Luis Izquierdo, "makes it possible to tackle the main types of cardiac disorders of hereditary origin and offers enormously valuable information to avoid the disease or to treat it much more efficiently. Until now, genetic tests related to hereditary heart disease have been very focused on certain pathologies, when it has been shown that there are many interactions between different heart conditions. myCardio allows a comprehensive approach to heart disease, with a new perspective that has been shown to be much more effective".

Advantages

Whole exome sequencing (WES) is the most appropriate tool to address the genetic heterogeneity present in inherited cardiovascular disease. Recent studies show a very significant improvement in diagnostic performance using exome sequencing compared to panels, since a high number of cases in which several mutations are recorded simultaneously are observed. The advantages of the exome are more prominent in those cases in which there is no high clinical suspicion, as well as those in which the patient has been recovered after an episode of sudden death.

The service covers the study of hereditary predisposition to Primary Cardiomyopathies, Metabolic Cardiomyopathies, Channelopathies and Arrhythmias, Syndromes with Vascular Affection, Rasopathies,other syndromes linked to cardiac pathology and other risk factors (Ischemic Heart Disease) such as Familial Hypercholesterolemia.

About Veritas Intercontinental

Veritas Intercontinental was founded in 2018 by Dr. Luis Izquierdo, Dr. Vincenzo Cirigliano and Javier de Echevarra, who have accumulated extensive experience in the field of genetics, diagnostics, and biotechnology, initially linked to Veritas Genetics, a company founded in 2014 by Prof. George Church, one of the pioneers in preventive medicine. Veritas was born with the aim of making genome sequencing and its clinical interpretation available to all citizens as a tool to prevent diseases and improve health and quality of life.

Since its inception, Veritas Intercontinental has led the activity and development of the Veritas market in Europe, Latin America, the Middle East, and Japan; with the aim of making genomics an everyday tool used for proactive healthcare management.

Based on its leadership in the application of preventive genomic medicine (myGenome), Veritas Intercontinental has expanded its offer to other areas such as perinatal medicine (myPrenatal -NIPT- and myNewborn -neonatal screening-), oncology (myCancerRisk), or the mentioned cardiovascular pathologies (myCardio), thus becoming the benchmark in advanced genomics services.

For further informationhttps://www.veritasint.com

Marta Pereiro[emailprotected]+34 915 623 675

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Veritas Intercontinental: Genetics makes it possible to identify cardiovascular genetic risk and prevent cardiac accidents such as those that have...

REYKJAVIK, Iceland, June 18, 2021 /PRNewswire/ -- Scientists from deCODE genetics have developed a predictor based on protein measurements in blood samples that predicts the time to all-cause death better than traditional risk factors.

In a paper published today in Communications Biology, scientists from deCODE genetics, a subsidiary of Amgen, describe how they developed predictor of how much is left of the life of a person.

Using a dataset of ~5000 protein measurements in 22,913 Icelanders, of whom 7,061 died during the study period, the scientists developed a predictor of the time to death that can outperform predictors based on multiple known risk factors. The predictor can identify the 5% at highest risk in a group of 60-80 year olds, where 88% died within ten years and the 5% at lowest risk where only 1% died within ten years.

The scientists explored how individual proteins associate with mortality and various causes of death and found most causes of death to have similar protein profiles. In particular, they found growth/differentiation factor 15 (GDF15), which has been associated with mortality and ageing before, to be an important predictor of all-cause mortality. Furthermore, they found that, on average, participants predicted at high risk of death within a short period of time had less grip strength and performed worse on an exercise tolerance test and a test of cognitive function than those predicted at lower risk.

"The predictor gives a good estimate of general health from a single blood draw," says Thjodbjorg Eiriksdottir scientist at deCODE genetics and author on the paper.

"This is pretty cool but also scary and hopefully somewhat useful", says Kari Stefansson a senior author on the paper . "This shows that our general health is reflected in the plasma proteome. Using just one blood sample per person you can easily compare large groups in a standardized way, for example, to estimate treatment effects in clinical trials."

Based in Reykjavik, Iceland, deCODE is a global leader in analyzing and understanding the human genome. Using its unique expertise in human genetics combined with growing expertise in transcriptomics and population proteomics and vast amount of phenotypic data, deCODE has discovered risk factors for dozens of common diseases and provided key insights into their pathogenesis. The purpose of understanding the genetics of disease is to use that information to create new means of diagnosing, treating and preventing disease. deCODE is a wholly-owned subsidiary of Amgen (NASDAQ: AMGN).

Contact:

Thora Kristin AsgeirsdottirPR and CommunicationsdeCODE geneticsthoraa@decode.is354 894 1909

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View original content to download multimedia:http://www.prnewswire.com/news-releases/decode-genetics-predicting-the-probability-of-death-301314856.html

SOURCE deCODE genetics

Company Codes: NASDAQ-NMS:AMGN

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deCODE genetics: Predicting the probability of death - BioSpace

'If genetic testing is done at the appropriate stage, some diseases can be prevented, cured or managed better.'

The Indian diagnostics industry has been rapidly evolving over the years and its emerged to be a key component of the healthcare segment. The arrival of Covid-19 pandemic pushed the healthcare industry to the sting worldwide by throwing many challenges, and therefore the diagnostic sector too witnessed a large transition during this phase. Whether its about keeping pace with the concept of telemedicine or addressing the change within the consumer psyche, the diagnostic sector has been facing different challenges with the increase of covid cases. As COVID-19 has spread, Indias diagnostic sector has been battling the virus at the forefront. In conversation with Financial Express Neeraj Gupta, Founder and CEO of Genes2me shared his experience and threw light on the challenges, learnings, and therefore the road ahead for the diagnostic businesses in India. Excerpts:

How has the diagnostic sector evolved since the arrival of Covid-19? Being an industry leader, what were some initial challenges you faced?Previously, the molecular diagnostic sector was not harnessed. We have seen that pandemic pushed the healthcare industry to the edge, but Indias diagnostic sector rose to meet the challenges. As COVID-19 has spread, Indias diagnostic sector has been combating the virus at the forefront. Initially, the Indian health care system was not fully prepared for such a massive crisis like COVID-19. We faced challenges regarding imports for raw materials and logistics due to global supply chain disruptions. This is also one of the reasons why we decided to use our expertise in molecular diagnostics and expand the portfolio into IVD manufacturing.

How has Genes2me come to the forefront during the pandemic? Tell us about your journey of delivering 40 Million covid test kits in India to date.

We take pride in the fact that Genes2Me has been working at the front line from the very first day of the pandemic. We developed several IVD kits, including Real-Time PCR Kits, VTM Kit, RNA Extraction Kits, NGS Kits and multiplexed genotyping assays for COVID-19 detection in a quick turnaround time.

Our ViralDtect-II Real-Time PCR Kit for COVID-19 has been a real turning point. It was the first Made in India Real-Time PCR Kit with comprehensive coverage of three genes that are specific to SARS-COV-2.

Also, there have been reports of new strains of SARS-COV-2 being detected. Genes2Me has developed a Unique Mutation Classifier assay that can rapidly differentiate 40 variants between 16 SARS-CoV-2 strains. This can help in the quick genetic screening of large sections of the population.

Genes2Me have been working tirelessly and have delivered more than 40 million COVID-19 testing kits to date. Also, to meet the sudden demand surge of the second Covid wave, we ramped our manufacturing facility from 9million per month to 6 million per week. In fact, during this time, Genes2Me contributed over 20% of the entire Indian testing needs for RT-PCR.

From where the idea of stepping into manufacturing IVD kits came under the Make in India initiative? What have been the challenges and opportunities?

When the pandemic hit us, not many diagnostic labs had the necessary infrastructure or accreditations to offer Covid testing facilities. As the pandemic gathered force, there was not only demand for faster testing but also testing in much higher volumes. The response to that struggle was the idea behind IVD kits under the Make in India initiative.The Indian government has taken progressive steps to boost the capacities of the domestic IVD sector. Genes2Me is also working to collaborate with the government and prestigious medical institutes to offer services on the innovative classifier panel of SARS-COV-2. In this manner, we can all be better prepared to face the challenges posed by this virus frequently changing genetic makeup.

What changes should diagnostic companies bring to fight the pandemic and meet the current market demand?

Post Covid-19, we have seen the entry of many companies into the Molecular Diagnostics Testing and Kit Manufacturing segment. Unfortunately, not many companies have been able to deliver quality genetic solutions in a fast turnaround time. This is evident from the fact that around 10-15 players used to compete in the Tender queries of IVD products till last year. But now, only 4-5 bidders are participating in the Tender queries as most of the companies have failed to satisfy customer expectations of Quality Product.

If you want to build a sustainable diagnostic company, you should maintain Quality Manufacturing and Testing Standards. Genes2Me has responded by building capacities and training faster to keep up with the surge without compromising the sensitivity of Genetic Solutions.

What have been some recent developments and future plans of Genes2me?

Genes2Me is vigorously working to leverage the large installed base of molecular testing platforms across the globe. With the help of our expertise and access to advanced technologies, we have developed several assays for Infectious diseases, Oncology and Reproductive Health in India. In the past, most of these test panels were import-dependent from other countries.

In addition, under the Make in India initiative, we are working to develop diverse nucleic acid research and diagnostics solutions along with NGS reagents for genome sequencing. Again, these solutions were dependent on import from different nations.

Genes2Me has also ramped up Covid-19 testing facilities by installing more infrastructure, hiring manpower and training them meticulously to ensure smooth functioning. Our advanced high throughput Real-Time PCR testing Lab at Gurgaon, Haryana, has an unmatched capacity to perform 8K-10K tests per day.

How do you see the future of Genetic Diagnostics in India?

India has a population of more than 1.26 billion people, with 26 million births occurring every year. This means that the burden of a genetic disease is very high. With the help of genetic diagnostics, many diseases can be predicted with great accuracy. If genetic testing is done at the appropriate stage, some diseases can be prevented, cured or managed better.

Genetics diagnostics in India is on the verge of transformation. There has been widespread awareness and recognition of the increasing incidence of congenital and hereditary genetic diseases in urban India. More and more people are seeking genetic testing and counselling services. Genetic diagnostic in India will evolve from a niche speciality to a wide scope of applications for complex diseases and personal use.

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Genetics diagnostics in India is on the verge of transformation: Neeraj Gupta, Founder and CEO of Genes2me - The Financial Express