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. 2014 Jul 17;511(7509):344-7.
doi: 10.1038/nature13394. Epub 2014 Jun 4.

Genome sequencing identifies major causes of severe intellectual disability

Christian Gilissen  1 , Jayne Y Hehir-Kwa  1 , Djie Tjwan Thung  2 , Maartje van de Vorst  2 , Bregje W M van Bon  2 , Marjolein H Willemsen  2 , Michael Kwint  2 , Irene M Janssen  2 , Alexander Hoischen  2 , Annette Schenck  2 , Richard Leach  3 , Robert Klein  3 , Rick Tearle  3 , Tan Bo  4 , Rolph Pfundt  2 , Helger G Yntema  2 , Bert B A de Vries  2 , Tjitske Kleefstra  2 , Han G Brunner  5 , Lisenka E L M Vissers  1 , Joris A Veltman  5
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Free article

Genome sequencing identifies major causes of severe intellectual disability

Christian Gilissen et al. Nature. .
Free article

Abstract

Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.

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