title: Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
abstract: 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.
authors.affiliation: 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.
authors.forename: Claire
authors.initials: C
authors.lastname: Redin
authors.affiliation: Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gérard
authors.affiliation: Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Lauer
authors.affiliation: Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Herenger
authors.affiliation: Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Muller
authors.affiliation: 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.
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authors.affiliation: Centre de Génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, CHU de Dijon, Dijon, France.
authors.forename: Alice
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authors.affiliation: Département de Génétique Médicale, Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Languedoc Roussillon, Hôpital Arnaud de Villeneuve, Montpellier, France.
authors.forename: Marjolaine
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authors.affiliation: Département de Génétique Médicale, Hospices Civils de Lyon, Bron, France.
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authors.affiliation: Centre de Génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, CHU de Dijon, Dijon, France.
authors.forename: Salima
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authors.affiliation: Plateforme de Biopuces et Séquençage, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
authors.forename: Stéphanie
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authors.affiliation: Plateforme de Biopuces et Séquençage, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
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authors.affiliation: Plateforme de Biopuces et Séquençage, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
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authors.affiliation: Plateforme de Biopuces et Séquençage, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
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authors.affiliation: Plateforme de Biopuces et Séquençage, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
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authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
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authors.affiliation: Département de Génétique, CHU de Hautepierre, Strasbourg, France.
authors.forename: Yves
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authors.affiliation: Départment de Biochimie et de Génétique, CHU d'Angers, Angers, France.
authors.forename: Magalie
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authors.affiliation: Départment de Biochimie et de Génétique, CHU d'Angers, Angers, France.
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authors.affiliation: Départment de Biochimie et de Génétique, CHU d'Angers, Angers, France.
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authors.affiliation: Laboratoire de Génétique Médicale, INSERM U1112, Faculté de Médecine de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Hélène
authors.initials: H
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authors.affiliation: Département de Génétique, CHU de Hautepierre, Strasbourg, France.
authors.forename: Bérénice
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authors.affiliation: CHU de Bordeaux, Génétique Médicale, Université de Bordeaux, Laboratoire MRGM, Bordeaux, France.
authors.forename: Marie-Ange
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authors.affiliation: Départment de Génétique Médicale, CHU de Rouen, Rouen, France.
authors.forename: Valérie
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authors.affiliation: Département de Génétique, CHU de Hautepierre, Strasbourg, France.
authors.forename: Elisabeth
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authors.affiliation: Service de Génétique Médicale, Centre De Référence Anomalies du Développement, CHU de Rennes, Rennes, France.
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authors.affiliation: Service de Génétique Médicale, Hôtel Dieu, Clermont-Ferrand, France.
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authors.affiliation: Départment de Génétique Médicale, CHU de Rouen, Rouen, France.
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authors.affiliation: Laboratoire de Biochimie, CHU de Nîmes, Nîmes, France.
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authors.affiliation: Unité de Génétique Clinique, CHU d'Amiens, Amiens, France.
authors.forename: Michèle
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authors.affiliation: Service de Génétique, Centre Hospitalier, Le Mans, France.
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authors.affiliation: CHU de Bordeaux, Génétique Médicale, Université de Bordeaux, Laboratoire MRGM, Bordeaux, France.
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authors.identifier: http://orcid.org/0000-0001-9271-3961
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authors.forename: Martine
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authors.forename: Pierre
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authors.affiliation: Département de Génétique Médicale, Hospices Civils de Lyon, Bron, France.
authors.forename: Patrick
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authors.affiliation: Service de Génétique Médicale, CHU de Nantes, Nantes, France.
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authors.lastname: Olivier-Faivre
authors.affiliation: 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 Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.affiliation: 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.
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mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
keywords: autism; causative; high-throughput sequencing; intellectual disability; mutation