• Claire Redin, Bénédicte Gérard, Julia Lauer, Yvan Herenger, Jean Muller, Angélique Quartier, Alice Masurel-Paulet, Marjolaine Willems, Gaétan Lesca, Salima El-Chehadeh, Stéphanie Le Gras, Serge Vicaire, Muriel Philipps, Michaël Dumas, Véronique Geoffroy, Claire Feger, Nicolas Haumesser, Yves Alembik, Magalie Barth, Dominique Bonneau, Estelle Colin, Hélène Dollfus, Bérénice Doray, Marie-Ange Delrue, Valérie Drouin-Garraud, Elisabeth Flori, Mélanie Fradin, Christine Francannet, Alice Goldenberg, Serge Lumbroso, Michèle Mathieu-Dramard, Dominique Martin-Coignard, Didier Lacombe, Gilles Morin, Anne Polge, Sylvie Sukno, Christel Thauvin-Robinet, Julien Thevenon, Martine Doco-Fenzy, David Genevieve, Pierre Sarda, Patrick Edery, Bertrand Isidor, Bernard Jost, Laurence Olivier-Faivre, Jean-Louis Mandel, and Amélie Piton.
• Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France Chaire de Génétique Humaine, Collège de France, Illkirch, France.
• J. Med. Genet. 2014 Nov 1; 51 (11): 724-36.

BackgroundIntellectual 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.MethodsWe 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.ResultsWe 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.ConclusionsWith 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.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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