Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin1,2. 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 undiagnosed3,4,5,6. 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.
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Data included in this manuscript have been deposited at the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home) under accession number EGAS00001000769.
We thank R. Drmanac, K. Albers, J. Goeman, D. Lugtenberg and P. N. Robinson for useful discussions, and M. Steehouwer, P. de Vries and W. Nillesen for technical support. This work was in part financially supported by grants from the Netherlands Organization for Scientific Research (912-12-109 to J.A.V., A.S. and B.B.A.d.V., 916-14-043 to C.G., 916-12-095 to A.H., 907-00-365 to T.K. and SH-271-13 to C.G. and J.A.V.) and the European Research Council (ERC Starting grant DENOVO 281964 to J.A.V.).
This file contains Supplementary Methods, Supplementary Tables 1-15 and Supplementary References.
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Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures
European Journal of Human Genetics (2019)