RT Journal Article
SR Electronic
T1 Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 609
OP 618
DO 10.1136/jmedgenet-2020-106901
VO 58
IS 9
A1 Gina Ravenscroft
A1 Joshua S Clayton
A1 Fathimath Faiz
A1 Padma Sivadorai
A1 Di Milnes
A1 Rob Cincotta
A1 Phillip Moon
A1 Ben Kamien
A1 Matthew Edwards
A1 Martin Delatycki
A1 Phillipa J Lamont
A1 Sophelia HS Chan
A1 Alison Colley
A1 Alan Ma
A1 Felicity Collins
A1 Lucinda Hennington
A1 Teresa Zhao
A1 George McGillivray
A1 Sondhya Ghedia
A1 Katherine Chao
A1 Anne O'Donnell-Luria
A1 Nigel G Laing
A1 Mark R Davis
YR 2021
UL http://jmg.bmj.com/content/58/9/609.abstract
AB 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.