Diagnostic exome sequencing in persons with severe intellectual disability.
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de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE
Diagnostic exome sequencing in persons with severe intellectual disability.
N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.
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- 23033978 [ View in PubMed]
- Abstract
BACKGROUND: The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity. METHODS: We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation. RESULTS: We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series. Thus, the total diagnostic yield was 16%, mostly involving de novo mutations. CONCLUSIONS: De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.).
DrugBank Data that Cites this Article
- Polypeptides
Name UniProt ID Glutamate receptor ionotropic, NMDA 2B Q13224 Details Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial P08559 Details Glutamate receptor ionotropic, NMDA 2A Q12879 Details Catenin beta-1 P35222 Details Prolow-density lipoprotein receptor-related protein 1 Q07954 Details Retinoblastoma-associated protein P06400 Details Ecto-NOX disulfide-thiol exchanger 2 Q16206 Details Calcium/calmodulin-dependent protein kinase type II subunit gamma Q13555 Details Cytoplasmic aconitate hydratase P21399 Details