Diagnostic exome sequencing in persons with severe intellectual disability.

Article Details


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.

PubMed ID
23033978 [ View in PubMed

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

NameUniProt ID
Glutamate receptor ionotropic, NMDA 2BQ13224Details
Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrialP08559Details
Glutamate receptor ionotropic, NMDA 2AQ12879Details
Catenin beta-1P35222Details
Prolow-density lipoprotein receptor-related protein 1Q07954Details
Retinoblastoma-associated proteinP06400Details
Ecto-NOX disulfide-thiol exchanger 2Q16206Details
Calcium/calmodulin-dependent protein kinase type II subunit gammaQ13555Details
Cytoplasmic aconitate hydrataseP21399Details