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Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome
  1. Christel Depienne1,2,3,
  2. Oriane Trouillard1,
  3. Isabelle Gourfinkel-An4,5,
  4. Cécile Saint-Martin2,
  5. Delphine Bouteiller2,
  6. Denis Graber6,
  7. Marie-Anne Barthez-Carpentier7,
  8. Agnès Gautier8,
  9. Nathalie Villeneuve9,
  10. Charlotte Dravet9,
  11. Marie-Odile Livet10,
  12. Clothilde Rivier-Ringenbach11,
  13. Claude Adam4,
  14. Sophie Dupont4,
  15. Stéphanie Baulac2,3,
  16. Delphine Héron12,
  17. Rima Nabbout5,13,
  18. Eric LeGuern1,2,3
  1. 1Unité Fonctionnelle de Neurogénétique Moléculaire et cellulaire, Département de Génétique et Cytogénétique, Centre de Génétique Moléculaire et chromosomique, AP-HP, GH Pitié-Salpêtrière, Paris, France
  2. 2INSERM U 975, Paris, France
  3. 3Université Pierre et Marie Curie, Centre de Recherche de l'institut du cerveau et de la moelle épinière, UMR_S975 Paris, France
  4. 4Pôle d'Epileptologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
  5. 5Centre de référence épilepsies rares, Paris, France
  6. 6Clinique de l'Enfant, Centre Hospitalier de la Rochelle, France
  7. 7Service de neuropédiatrique, Hôpital Gatien de Clocheville, CHRU de Tours, France
  8. 8Clinique Médicale Pédiatrique, Hôpital Mère-Enfant, CHU de Nantes, France
  9. 9Service de Neurologie, Hôpital Henri Gastaut, Marseille, France
  10. 10Service de Pédiatrie, Centre Hospitalier du pays d'Aix, Aix-en-Provence, France
  11. 11Service de pédiatre-Néonatologie, Centre Hospitalier de Villefranche s/Saone, France
  12. 12Unité Fonctionnelle de Génétique Clinique, Département de Génétique et Cytogénétique, AP-HP, GH Pitié-Salpêtrière, Paris, France
  13. 13Département de Neuropédiatrie, AP-HP, Inserm U663, Hôpital Necker-Enfants malades, Paris, France
  1. Correspondence to Dr Christel Depienne, INSERM U975 (CRicm), Bâtiment Pharmacie 4ème étage, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'hôpital,75013 Paris, France; christel.depienne{at}upmc.fr

Abstract

Background Mutations in SCN1A can cause genetic epilepsy with febrile seizures plus (GEFS+, inherited missense mutations) or Dravet syndrome (DS, de novo mutations of all types). Although the mutational spectra are distinct, these disorders share major features and 10% of DS patients have an inherited SCN1A mutation.

Objectives and patients 19 selected families with at least one DS patient were studied to describe the mechanisms accounting for inherited SCN1A mutations in DS. The mutation identified in the DS probands was searched in available parents and relatives and quantified in the blood cells of the transmitting parent using quantitative allele specific assays.

Results Mosaicism in the blood cells of the transmitting parent was demonstrated in 12 cases and suspected in another case. The proportion of mutated allele in the blood varied from 0.04–85%. In the six remaining families, six novel missense mutations were associated with autosomal dominant variable GEFS+ phenotypes including DS as the more severe clinical picture.

Conclusion The results indicate that mosaicism is found in at least 7% of families with DS. In the remaining cases (6/19, 32%), the patients were part of multiplex GEFS+ families and seemed to represent the extreme end of the GEFS+ clinical spectrum. In this latter case, additional genetic or environmental factors likely modulate the severity of the expression of the mutation.

  • Clinical genetics
  • genetic screening/counselling
  • molecular genetics
  • epilepsy and seizures

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Footnotes

  • Funding Other Funders: AP-HP, INSERM.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Pitié-Salpêtrière Hospital, Paris.

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

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