TY - JOUR T1 - Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics JF - Journal of Medical Genetics JO - J Med Genet SP - 609 LP - 618 DO - 10.1136/jmedgenet-2020-106901 VL - 58 IS - 9 AU - Gina Ravenscroft AU - Joshua S Clayton AU - Fathimath Faiz AU - Padma Sivadorai AU - Di Milnes AU - Rob Cincotta AU - Phillip Moon AU - Ben Kamien AU - Matthew Edwards AU - Martin Delatycki AU - Phillipa J Lamont AU - Sophelia HS Chan AU - Alison Colley AU - Alan Ma AU - Felicity Collins AU - Lucinda Hennington AU - Teresa Zhao AU - George McGillivray AU - Sondhya Ghedia AU - Katherine Chao AU - Anne O'Donnell-Luria AU - Nigel G Laing AU - Mark R Davis Y1 - 2021/09/01 UR - http://jmg.bmj.com/content/58/9/609.abstract N2 - Background Fetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions.Methods We performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome. This sequencing was a combination of bespoke neurogenetic disease gene panels and whole exome sequencing. Only class 4 and 5 variants were reported, except for two cases where the identified variants of unknown significance (VUS) are most likely to be causative for the observed phenotype. Co-segregation studies and confirmation of variants identified by NGS were performed where possible. Functional genomics was performed as required.Results Of the 190 probands, 81 received an accurate genetic diagnosis. All except two of these cases harboured class 4 and/or 5 variants based on the American College of Medical Genetics and Genomics guidelines. We identified phenotypic expansions associated with CACNA1S, CHRNB1, GMPPB and STAC3. We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations—SMPD4.Conclusions Comprehensive gene panels give a diagnosis for a substantial proportion (42%) of fetal akinesia and arthrogryposis cases, even in an unselected cohort. Recently identified genes account for a relatively large proportion, 32%, of the diagnoses. Diagnostic-research collaboration was critical to the diagnosis and variant interpretation in many cases, facilitated genotype-phenotype expansions and reclassified VUS through functional genomics.Data are available on reasonable request. ER -