Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics.

2021

Ravenscroft, Gina

Clayton, Joshua S

Faiz, Fathimath

Sivadorai, Padma

Milnes, Di

Cincotta, Rob

Moon, Phillip

Kamien, Ben

Edwards, Matthew

Delatycki, Martin B

Lamont, Phillipa J

Chan, Sophelia Hs

Colley, Alison

Ma, Alan

Collins, Felicity

Hennington, Lucinda

Zhao, Teresa

McGillivray, George

Ghedia, Sondhya

Chao, Katherine

O'Donnell-Luria, Anne

Laing, Nigel G

Davis, Mark R

clinical genetics

molecular genetics

neuromuscular disease

Journal Article

0000-0003-3634-211X

0000-0001-8437-8120

10.1136/jmedgenet-2020-106901

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. 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. 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. 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.

link

Journal of Medical Genetics 2021; 58(9): 609-618

Journal of Medical Genetics