TY - JOUR T1 - Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing JF - Journal of Medical Genetics JO - J Med Genet SP - 724 LP - 736 DO - 10.1136/jmedgenet-2014-102554 VL - 51 IS - 11 AU - Claire Redin AU - Bénédicte Gérard AU - Julia Lauer AU - Yvan Herenger AU - Jean Muller AU - Angélique Quartier AU - Alice Masurel-Paulet AU - Marjolaine Willems AU - Gaétan Lesca AU - Salima El-Chehadeh AU - Stéphanie Le Gras AU - Serge Vicaire AU - Muriel Philipps AU - Michaël Dumas AU - Véronique Geoffroy AU - Claire Feger AU - Nicolas Haumesser AU - Yves Alembik AU - Magalie Barth AU - Dominique Bonneau AU - Estelle Colin AU - Hélène Dollfus AU - Bérénice Doray AU - Marie-Ange Delrue AU - Valérie Drouin-Garraud AU - Elisabeth Flori AU - Mélanie Fradin AU - Christine Francannet AU - Alice Goldenberg AU - Serge Lumbroso AU - Michèle Mathieu-Dramard AU - Dominique Martin-Coignard AU - Didier Lacombe AU - Gilles Morin AU - Anne Polge AU - Sylvie Sukno AU - Christel Thauvin-Robinet AU - Julien Thevenon AU - Martine Doco-Fenzy AU - David Genevieve AU - Pierre Sarda AU - Patrick Edery AU - Bertrand Isidor AU - Bernard Jost AU - Laurence Olivier-Faivre AU - Jean-Louis Mandel AU - Amélie Piton Y1 - 2014/11/01 UR - http://jmg.bmj.com/content/51/11/724.abstract N2 - 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. ER -