1. Genome sequencing identifies major causes of severe intellectual disability
- Author
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Gilissen, Christian, Hehir-Kwa, Jayne Y., Thung, Djie Tjwan, van de Vorst, Maartje, van Bon, Bregje W.M., Willemsen, Marjolein H., Kwint, Michael, Janssen, Irene M., Hoischen, Alexander, Schenck, Annette, Leach, Richard, Klein, Robert, Tearle, Rick, Bo, Tan, Pfundt, Rolph, Yntema, Helger G., de Vries, Bert B.A., Kleefstra, Tjitske, Brunner, Han G., Vissers, Lisenka E.L.M., and Veltman, Joris A.
- Subjects
Nucleotide sequencing -- Physiological aspects -- Methods ,Gene mutations -- Identification and classification ,Mental retardation -- Causes of -- Genetic aspects ,DNA sequencing -- Physiological aspects -- Methods ,Genetic variation -- Identification and classification ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - 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 denovo 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 denovo 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 denovo 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., Whole-genome sequencing (WGS) is considered to be the most comprehensive genetic test so far (7), but widespread application to patient diagnostics has been hampered by challenges in data analysis, the [...]
- Published
- 2014