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Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics
  1. Gina Ravenscroft1,2,
  2. Joshua S Clayton1,2,
  3. Fathimath Faiz3,
  4. Padma Sivadorai3,
  5. Di Milnes4,
  6. Rob Cincotta5,
  7. Phillip Moon6,
  8. Ben Kamien7,8,
  9. Matthew Edwards8,
  10. Martin Delatycki9,
  11. Phillipa J Lamont10,
  12. Sophelia HS Chan11,
  13. Alison Colley12,
  14. Alan Ma13,
  15. Felicity Collins14,
  16. Lucinda Hennington15,16,17,
  17. Teresa Zhao9,
  18. George McGillivray9,
  19. Sondhya Ghedia18,
  20. Katherine Chao19,
  21. Anne O'Donnell-Luria19,
  22. Nigel G Laing1,2,3,
  23. Mark R Davis3
  1. 1 Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia
  2. 2 Faculty of Health and Medical Sciences, University of Western Australia, Nedlands, Western Australia, Australia
  3. 3 PathWest Diagnostic Genomics, Nedlands, Western Australia, Australia
  4. 4 Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
  5. 5 Maternal and Fetal Medicine, Mater Mothers’ Hospital, Brisbane, Queensland, Australia
  6. 6 Department of Obstetrics, Redland Hospital, Cleveland, Queensland, Australia
  7. 7 Genetic Services WA, Women and Newborn Heath Service, Subiaco, Western Australia, Australia
  8. 8 Hunter Genetics, Hunter New England Health, New Lambton, New South Wales, Australia
  9. 9 Victorian Clinical Genetics Service, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
  10. 10 Neurology, Royal Perth Hospital, Perth, Western Australia, Australia
  11. 11 Paediatric Neurology Division, Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong
  12. 12 Clinical Genetics Services SWSLHD, Liverpool Hospital, Liverpool, New South Wales, Australia
  13. 13 Department of Clinical Genetics, Children’s Hospital Westmead, Sydney, New South Wales, Australia
  14. 14 Clinical Genetics Department, Western Sydney Genetics Program, Children’s Hospitalat Westmead, Westmead, New South Wales, Australia
  15. 15 Mercy Health, Mercy Hospital for Women, Heidelberg, Victoria, Australia
  16. 16 Austin Health, Melbourne, Victoria, Australia
  17. 17 Alfred Health, Melbourne, Victoria, Australia
  18. 18 Department of Clinical Genetics, Royal North Shore Hospital, Sydney, New South Wales, Australia
  19. 19 Center for Mendelian Genomics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
  1. Correspondence to Dr Gina Ravenscroft, UWA, Nedlands, Australian Capital Territory, Australia; gina.ravenscroft{at}


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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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.