{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:15:39Z","timestamp":1793394939465,"version":"4.5.0"},"reference-count":59,"publisher":"BMJ","issue":"9","funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2020,7,5]]},"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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 <jats:italic>CACNA1S, CHRNB1, GMPPB<\/jats:italic> and <jats:italic>STAC3<\/jats:italic>. We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations<jats:italic>\u2014SMPD4<\/jats:italic>.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2020-106901","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T17:26:03Z","timestamp":1602782763000},"page":"609-618","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":70,"title":["Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics"],"prefix":"10.1136","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3634-211X","authenticated-orcid":false,"given":"Gina","family":"Ravenscroft","sequence":"first","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia"},{"name":"Faculty of Health and Medical Sciences, University 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