Article Text

Original article
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
  1. Claire Redin1,2,
  2. Bénédicte Gérard3,
  3. Julia Lauer3,
  4. Yvan Herenger3,
  5. Jean Muller1,3,
  6. Angélique Quartier1,2,
  7. Alice Masurel-Paulet4,
  8. Marjolaine Willems5,
  9. Gaétan Lesca6,
  10. Salima El-Chehadeh4,
  11. Stéphanie Le Gras7,
  12. Serge Vicaire7,
  13. Muriel Philipps7,
  14. Michaël Dumas7,
  15. Véronique Geoffroy8,
  16. Claire Feger7,
  17. Nicolas Haumesser1,2,
  18. Yves Alembik9,
  19. Magalie Barth10,
  20. Dominique Bonneau10,
  21. Estelle Colin10,
  22. Hélène Dollfus11,
  23. Bérénice Doray9,
  24. Marie-Ange Delrue12,
  25. Valérie Drouin-Garraud13,
  26. Elisabeth Flori9,
  27. Mélanie Fradin14,
  28. Christine Francannet15,
  29. Alice Goldenberg13,
  30. Serge Lumbroso16,
  31. Michèle Mathieu-Dramard17,
  32. Dominique Martin-Coignard18,
  33. Didier Lacombe12,
  34. Gilles Morin17,
  35. Anne Polge16,
  36. Sylvie Sukno19,
  37. Christel Thauvin-Robinet4,
  38. Julien Thevenon4,
  39. Martine Doco-Fenzy20,
  40. David Genevieve5,
  41. Pierre Sarda5,
  42. Patrick Edery6,
  43. Bertrand Isidor21,
  44. Bernard Jost7,
  45. Laurence Olivier-Faivre4,
  46. Jean-Louis Mandel1,2,3,
  47. Amélie Piton1,2
  1. 1Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France
  2. 2Chaire de Génétique Humaine, Collège de France, Illkirch, France
  3. 3Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  4. 4Centre de Génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, CHU de Dijon, Dijon, France
  5. 5Département de Génétique Médicale, Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Languedoc Roussillon, Hôpital Arnaud de Villeneuve, Montpellier, France
  6. 6Département de Génétique Médicale, Hospices Civils de Lyon, Bron, France
  7. 7Plateforme de Biopuces et Séquençage, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France
  8. 8Plateforme de Bioinformatique de Strasbourg (BIPS), IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France
  9. 9Département de Génétique, CHU de Hautepierre, Strasbourg, France
  10. 10Départment de Biochimie et de Génétique, CHU d'Angers, Angers, France
  11. 11Laboratoire de Génétique Médicale, INSERM U1112, Faculté de Médecine de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  12. 12CHU de Bordeaux, Génétique Médicale, Université de Bordeaux, Laboratoire MRGM, Bordeaux, France
  13. 13Départment de Génétique Médicale, CHU de Rouen, Rouen, France
  14. 14Service de Génétique Médicale, Centre De Référence Anomalies du Développement, CHU de Rennes, Rennes, France
  15. 15Service de Génétique Médicale, Hôtel Dieu, Clermont-Ferrand, France
  16. 16Laboratoire de Biochimie, CHU de Nîmes, Nîmes, France
  17. 17Unité de Génétique Clinique, CHU d'Amiens, Amiens, France
  18. 18Service de Génétique, Centre Hospitalier, Le Mans, France
  19. 19Service de Neuropédiatrie, Hôpital Saint Vincent de Paul, Groupe Hospitalier de l'Institut Catholique Lillois, Faculté Libre de Médecine, Lille, France
  20. 20Service de Génétique, CHU de Reims, EA3801, Reims, France
  21. 21Service de Génétique Médicale, CHU de Nantes, Nantes, France
  1. Correspondence to Amelie Piton, Translational Medicine & Neurogenetic, 67 400 Illkirch, France; amelie.piton{at} Jean-Louis Mandel, Translational Medecine & Neurogenetic, 67 400 Illkirch, France;


Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation.

Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases.

Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders.

Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.

  • intellectual disability
  • mutation
  • high-throughput sequencing
  • autism
  • causative

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