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.
- neuromuscular disease
- clinical genetics
- molecular genetics
Data availability statement
Data are available on reasonable request.
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Contributors GR, NGL, MRD conceived the study. JSC, FF and PS performed experiments. TZ, KC, AHO'D-L, GR, MRD, JSC, FF and PS analysed data. DM, RC, PM, BK, ME, MD, PJL, SH-SC, AM, AC, FC, LH, GMcG and SG contributed clinical data. GR wrote the manuscript. All authors approved the final manuscript.
Funding This work was supported by the Australian National Health and Medical Research Council (NHMRC) Fellowships APP1122952 and APP1117510 to GR and NGL, NHMRC project grant APP1080587 to GR and NGL, the Association Francaise contre les Myopathies (18724) to GR. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.