Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome | European Journal of Human Genetics – Nature.com

Disorders of the first and second branchial arches include Treacher Collins syndrome (TCS; MIM 154500), auricocondylar syndrome (ACS; MIM 602483), mandibulofacial dysostosis, Guion-Almeida type (MIM 610536), branchio-oto-renal syndrome (BOR; MIM 113650, 610896), Stickler syndrome (MIM 108300) and hemifacial microsomia/oculo-auriculo-vertebral spectrum (HFM/OAVS; MIM 164210). These disorders are thought to result from a combination of inadequate migration and formation of facial mesenchyme during early embryonic life [1]. In TCS, ACS, BOR and Stickler syndrome molecular pathways have been established, however for the spectrum of disease encompassed by OAVS, the full molecular etiology of the condition is the subject of ongoing investigation.

OAVS, also known as Goldenhar syndrome or hemifacial/craniofacial microsomia, is a heterogeneous and complex group of disorders [2]. Craniofacial appearances range from subtle facial asymmetry to HFM or orofacial clefts, preauricular skin tags to microtia and anotia, and epibulbar dermoids to micropthalmia and coloboma [3]. Extracranial defects of the cardiac, renal, vertebral and central nervous systems are reported [3,4,5]. This marked phenotypic variability and a lack of consensus on minimum diagnostic criteria has resulted in considerable discrepancy in reported prevalence, but it is generally now accepted at 1 in 5600 [4].

The etiology of OAVS is still largely unknown and felt to be multifactorial due to both environmental (maternal diabetes, antenatal exposure to vasoactive medications, smoking and twinning) and genetic factors during early embryogenesis [4]. With the widespread adoption of exome or genome sequencing, several genes have now been associated with OAVS [6,7,8,9,10,11], although many have only been identified through segregation in multi-generational single families. Most recently, a large exome/genome sequencing effort of trios identified haploinsufficient variants in SF3B2 in multiple families segregating OAVS [12]. Variants were identified in 3% of sporadic and 25% of familial cases, indicating that while SF3B2 genetic alterations are the most common cause of OAVS identified to date, there is wide genetic heterogeneity for this condition.

The PAX-SIX-EYA-DACH (PSED) network is involved in a variety of developmental processes including roles in morphogenesis of the branchial arches, which acts as the developmental basis for many of the clinical features of OAVS. A proposed mechanism for OAVS is that altered signaling networks cause disrupted migration of cranial neural crest cells, which are essential for normal facial mesenchymal tissue development [4].

The PAX family encode nuclear transcription factors involved in embryogenesis in vertebrates, with five out of the nine PAX genes associated with congenital disorders in humans to date. Biallelic hypomorphic or loss of function variants in PAX1 have been described in several families with otofaciocervical syndrome type 2 (OTFCS2; MIM 615560) [13,14,15,16]. In severe cases, patients can also have severe combined immune deficiency, caused by underdevelopment or absence of the thymus [13].

Here we describe a novel dominant PAX1 variant segregating with full penetrance but variable expressivity in a family with OAVS. All family members are affected with mild but definitive features of OAVS including HFM, misshapen ears and preauricular pits. Imaging on the three available family members did not detect any vertebral anomalies. Our findings suggest a novel cause of OAVS and confirm that heterozygous variants in PAX1 can cause a clinically overt genetic disorder.

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Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome | European Journal of Human Genetics - Nature.com