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Original research
De novo mutations of SCN1A are responsible for arthrogryposis broadening the SCN1A-related phenotypes
  1. Dana Jaber1,
  2. Cyril Gitiaux2,
  3. Sophie Blesson3,
  4. Florent Marguet4,5,
  5. David Buard1,
  6. Maritzaida Varela Salgado1,
  7. Anna Kaminska6,
  8. Julien Saada7,
  9. Catherine Fallet-Bianco8,
  10. Jelena Martinovic9,
  11. Annie Laquerriere4,5,
  12. Judith Melki1,10
  1. 1Institut National de la Santé et de la Recherche Médicale (Inserm), UMR-1195, Université Paris Saclay, Le Kremlin Bicêtre, 94276, France
  2. 2Service de Neurophysiologie Clinique, Centre de référence des maladies neuromusculaires, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, 75015, France
  3. 3Service de Génétique, Unité de Génétique Clinique, CHRU de Tours, Hôpital Bretonneau, Tours, 37044, France
  4. 4Laboratoire de Pathologie, CHU de Rouen and Normandie Univ, Rouen, 76000, France
  5. 5INSERM, Laboratoire NeoVasc ERI28, Rouen, 76000, France
  6. 6Neurophysiology Department, Necker-Enfants Malades Hospital, Assistance publique-Hôpitaux de Paris, Paris, 75015, France
  7. 7Département d’Obstétrique et Gynécologie, Hôpital Antoine-Béclère, Assistance publique-Hôpitaux de Paris, Clamart, 92140, France
  8. 8Département de Pathologie, CHU Sainte-Justine, Université de Montréal, Quebec, H3T 1C5, Quebec, Canada
  9. 9Unité de Foetopathologie, Hôpital Antoine-Béclère, Assistance publique-Hôpitaux de Paris, Clamart, 92140, France
  10. 10Unité de Génétique Médicale, Centre de référence des anomalies du développement et syndromes malformatifs d’Île-de-France, Assistance publique-Hôpitaux de Paris, Le Kremlin Bicêtre, 94276, France
  1. Correspondence to Professor Judith Melki, INSERM, Paris 94276, France; judith.melki{at}


Background Arthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. SCN1A encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of SCN1A are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in SCN1A in three unrelated individuals with AMC.

Methods Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo.

Results AMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that SCN1A is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement.

Conclusion We show for the first time that SCN1A variants are responsible for early-onset motor defect leading to AMC indicating a critical role of SCN1A in prenatal motor development and broadening the phenotypic spectrum of variants in SCN1A.

  • human genetics
  • genomics
  • neuromuscular diseases
  • epilepsy
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  • Contributors DJ, DB and MVS conducted molecular analyses. CG, SB, FM, JS, CF-B, JMa and AL recruited and phenotyped the patients. CG conducted electrophysiological studies and contributed to writing the manuscript. AK conducted EEG studies and contributed to writing the manuscript. AL contributed to writing the manuscript. JMe designed the study, performed bioinformatics analysis of whole-exome sequencing data and wrote the manuscript. All authors reviewed the manuscript.

  • Funding This work was supported by a grant from the Association Française contre les Myopathies (AFM, R16070LL), the Agence de Biomedecine (2016) and the Institut National de la Santé et de la Recherche Médicale (Inserm) to JMe.

  • Competing interests None declared.

  • Patient consent for publication Parental/guardian consent obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information. All data relevant to the study are included in the article and are available.

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