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J Med Genet. 2014 Nov;51(11):724-36. doi: 10.1136/jmedgenet-2014-102554. Epub 2014 Aug 28.

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

Author information

1
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.
2
Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
3
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.
4
Centre de Génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, CHU de Dijon, Dijon, France.
5
Département de Génétique Médicale, Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Languedoc Roussillon, Hôpital Arnaud de Villeneuve, Montpellier, France.
6
Département de Génétique Médicale, Hospices Civils de Lyon, Bron, France.
7
Plateforme de Biopuces et Séquençage, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
8
Plateforme de Bioinformatique de Strasbourg (BIPS), IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
9
Département de Génétique, CHU de Hautepierre, Strasbourg, France.
10
Départment de Biochimie et de Génétique, CHU d'Angers, Angers, France.
11
Laboratoire de Génétique Médicale, INSERM U1112, Faculté de Médecine de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
12
CHU de Bordeaux, Génétique Médicale, Université de Bordeaux, Laboratoire MRGM, Bordeaux, France.
13
Départment de Génétique Médicale, CHU de Rouen, Rouen, France.
14
Service de Génétique Médicale, Centre De Référence Anomalies du Développement, CHU de Rennes, Rennes, France.
15
Service de Génétique Médicale, Hôtel Dieu, Clermont-Ferrand, France.
16
Laboratoire de Biochimie, CHU de Nîmes, Nîmes, France.
17
Unité de Génétique Clinique, CHU d'Amiens, Amiens, France.
18
Service de Génétique, Centre Hospitalier, Le Mans, France.
19
Service de Neuropédiatrie, Hôpital Saint Vincent de Paul, Groupe Hospitalier de l'Institut Catholique Lillois, Faculté Libre de Médecine, Lille, France.
20
Service de Génétique, CHU de Reims, EA3801, Reims, France.
21
Service de Génétique Médicale, CHU de Nantes, Nantes, France.
22
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.

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.

KEYWORDS:

autism; causative; high-throughput sequencing; intellectual disability; mutation

PMID:
25167861
PMCID:
PMC4215287
DOI:
10.1136/jmedgenet-2014-102554
[Indexed for MEDLINE]
Free PMC Article

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