Genome sequencing identifies major causes of severe intellectual disability

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

731 Citations (Web of Science)

Abstract

Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin(1,2). 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(3-6). 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.
Original languageEnglish
Pages (from-to)344-+
JournalNature
Volume511
Issue number7509
DOIs
Publication statusPublished - 17 Jul 2014

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