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Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

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 costl...

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Autores principales: Redin, Claire, Gérard, Bénédicte, Lauer, Julia, Herenger, Yvan, Muller, Jean, Quartier, Angélique, Masurel-Paulet, Alice, Willems, Marjolaine, Lesca, Gaétan, El-Chehadeh, Salima, Le Gras, Stéphanie, Vicaire, Serge, Philipps, Muriel, Dumas, Michaël, Geoffroy, Véronique, Feger, Claire, Haumesser, Nicolas, Alembik, Yves, Barth, Magalie, Bonneau, Dominique, Colin, Estelle, Dollfus, Hélène, Doray, Bérénice, Delrue, Marie-Ange, Drouin-Garraud, Valérie, Flori, Elisabeth, Fradin, Mélanie, Francannet, Christine, Goldenberg, Alice, Lumbroso, Serge, Mathieu-Dramard, Michèle, Martin-Coignard, Dominique, Lacombe, Didier, Morin, Gilles, Polge, Anne, Sukno, Sylvie, Thauvin-Robinet, Christel, Thevenon, Julien, Doco-Fenzy, Martine, Genevieve, David, Sarda, Pierre, Edery, Patrick, Isidor, Bertrand, Jost, Bernard, Olivier-Faivre, Laurence, Mandel, Jean-Louis, Piton, Amélie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215287/
https://www.ncbi.nlm.nih.gov/pubmed/25167861
http://dx.doi.org/10.1136/jmedgenet-2014-102554
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author Redin, Claire
Gérard, Bénédicte
Lauer, Julia
Herenger, Yvan
Muller, Jean
Quartier, Angélique
Masurel-Paulet, Alice
Willems, Marjolaine
Lesca, Gaétan
El-Chehadeh, Salima
Le Gras, Stéphanie
Vicaire, Serge
Philipps, Muriel
Dumas, Michaël
Geoffroy, Véronique
Feger, Claire
Haumesser, Nicolas
Alembik, Yves
Barth, Magalie
Bonneau, Dominique
Colin, Estelle
Dollfus, Hélène
Doray, Bérénice
Delrue, Marie-Ange
Drouin-Garraud, Valérie
Flori, Elisabeth
Fradin, Mélanie
Francannet, Christine
Goldenberg, Alice
Lumbroso, Serge
Mathieu-Dramard, Michèle
Martin-Coignard, Dominique
Lacombe, Didier
Morin, Gilles
Polge, Anne
Sukno, Sylvie
Thauvin-Robinet, Christel
Thevenon, Julien
Doco-Fenzy, Martine
Genevieve, David
Sarda, Pierre
Edery, Patrick
Isidor, Bertrand
Jost, Bernard
Olivier-Faivre, Laurence
Mandel, Jean-Louis
Piton, Amélie
author_facet Redin, Claire
Gérard, Bénédicte
Lauer, Julia
Herenger, Yvan
Muller, Jean
Quartier, Angélique
Masurel-Paulet, Alice
Willems, Marjolaine
Lesca, Gaétan
El-Chehadeh, Salima
Le Gras, Stéphanie
Vicaire, Serge
Philipps, Muriel
Dumas, Michaël
Geoffroy, Véronique
Feger, Claire
Haumesser, Nicolas
Alembik, Yves
Barth, Magalie
Bonneau, Dominique
Colin, Estelle
Dollfus, Hélène
Doray, Bérénice
Delrue, Marie-Ange
Drouin-Garraud, Valérie
Flori, Elisabeth
Fradin, Mélanie
Francannet, Christine
Goldenberg, Alice
Lumbroso, Serge
Mathieu-Dramard, Michèle
Martin-Coignard, Dominique
Lacombe, Didier
Morin, Gilles
Polge, Anne
Sukno, Sylvie
Thauvin-Robinet, Christel
Thevenon, Julien
Doco-Fenzy, Martine
Genevieve, David
Sarda, Pierre
Edery, Patrick
Isidor, Bertrand
Jost, Bernard
Olivier-Faivre, Laurence
Mandel, Jean-Louis
Piton, Amélie
author_sort Redin, Claire
collection PubMed
description 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.
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spelling pubmed-42152872014-11-05 Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin, Claire Gérard, Bénédicte Lauer, Julia Herenger, Yvan Muller, Jean Quartier, Angélique Masurel-Paulet, Alice Willems, Marjolaine Lesca, Gaétan El-Chehadeh, Salima Le Gras, Stéphanie Vicaire, Serge Philipps, Muriel Dumas, Michaël Geoffroy, Véronique Feger, Claire Haumesser, Nicolas Alembik, Yves Barth, Magalie Bonneau, Dominique Colin, Estelle Dollfus, Hélène Doray, Bérénice Delrue, Marie-Ange Drouin-Garraud, Valérie Flori, Elisabeth Fradin, Mélanie Francannet, Christine Goldenberg, Alice Lumbroso, Serge Mathieu-Dramard, Michèle Martin-Coignard, Dominique Lacombe, Didier Morin, Gilles Polge, Anne Sukno, Sylvie Thauvin-Robinet, Christel Thevenon, Julien Doco-Fenzy, Martine Genevieve, David Sarda, Pierre Edery, Patrick Isidor, Bertrand Jost, Bernard Olivier-Faivre, Laurence Mandel, Jean-Louis Piton, Amélie J Med Genet Cognitive and Behavioural Genetics 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. BMJ Publishing Group 2014-11 2014-08-28 /pmc/articles/PMC4215287/ /pubmed/25167861 http://dx.doi.org/10.1136/jmedgenet-2014-102554 Text en 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 This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
spellingShingle Cognitive and Behavioural Genetics
Redin, Claire
Gérard, Bénédicte
Lauer, Julia
Herenger, Yvan
Muller, Jean
Quartier, Angélique
Masurel-Paulet, Alice
Willems, Marjolaine
Lesca, Gaétan
El-Chehadeh, Salima
Le Gras, Stéphanie
Vicaire, Serge
Philipps, Muriel
Dumas, Michaël
Geoffroy, Véronique
Feger, Claire
Haumesser, Nicolas
Alembik, Yves
Barth, Magalie
Bonneau, Dominique
Colin, Estelle
Dollfus, Hélène
Doray, Bérénice
Delrue, Marie-Ange
Drouin-Garraud, Valérie
Flori, Elisabeth
Fradin, Mélanie
Francannet, Christine
Goldenberg, Alice
Lumbroso, Serge
Mathieu-Dramard, Michèle
Martin-Coignard, Dominique
Lacombe, Didier
Morin, Gilles
Polge, Anne
Sukno, Sylvie
Thauvin-Robinet, Christel
Thevenon, Julien
Doco-Fenzy, Martine
Genevieve, David
Sarda, Pierre
Edery, Patrick
Isidor, Bertrand
Jost, Bernard
Olivier-Faivre, Laurence
Mandel, Jean-Louis
Piton, Amélie
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
title Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
title_full Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
title_fullStr Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
title_full_unstemmed Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
title_short Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
title_sort efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing
topic Cognitive and Behavioural Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215287/
https://www.ncbi.nlm.nih.gov/pubmed/25167861
http://dx.doi.org/10.1136/jmedgenet-2014-102554
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