RT Journal Article
SR Electronic
T1 Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 724
OP 736
DO 10.1136/jmedgenet-2014-102554
VO 51
IS 11
A1 Claire Redin
A1 Bénédicte Gérard
A1 Julia Lauer
A1 Yvan Herenger
A1 Jean Muller
A1 Angélique Quartier
A1 Alice Masurel-Paulet
A1 Marjolaine Willems
A1 Gaétan Lesca
A1 Salima El-Chehadeh
A1 Stéphanie Le Gras
A1 Serge Vicaire
A1 Muriel Philipps
A1 Michaël Dumas
A1 Véronique Geoffroy
A1 Claire Feger
A1 Nicolas Haumesser
A1 Yves Alembik
A1 Magalie Barth
A1 Dominique Bonneau
A1 Estelle Colin
A1 Hélène Dollfus
A1 Bérénice Doray
A1 Marie-Ange Delrue
A1 Valérie Drouin-Garraud
A1 Elisabeth Flori
A1 Mélanie Fradin
A1 Christine Francannet
A1 Alice Goldenberg
A1 Serge Lumbroso
A1 Michèle Mathieu-Dramard
A1 Dominique Martin-Coignard
A1 Didier Lacombe
A1 Gilles Morin
A1 Anne Polge
A1 Sylvie Sukno
A1 Christel Thauvin-Robinet
A1 Julien Thevenon
A1 Martine Doco-Fenzy
A1 David Genevieve
A1 Pierre Sarda
A1 Patrick Edery
A1 Bertrand Isidor
A1 Bernard Jost
A1 Laurence Olivier-Faivre
A1 Jean-Louis Mandel
A1 Amélie Piton
YR 2014
UL http://jmg.bmj.com/content/51/11/724.abstract
AB 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.