Genome sequencing identifies major causes of severe intellectual disability. C. Gilissen1, J. Y. Hehir-Kwa1, D. Thung1, M. van de Vorst1, B. W. M. van Bon1, M. H. Willemsen1, M. Kwint1, I. M. Janssen1, A. Hoischen1, A. Schenck1, R. Leach2, R. Klein2, R. Tearle2, T. Bo1,3, R. Pfundt1, H. G. Yntema1, B. B. A. de Vries1, T. Kleefstra1, H. G. Brunner1,4, L. E. L. M. Vissers1, J. A. Veltman1,4 1) Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; 2) Complete Genomics Inc., Mountain View, CA, USA; 3) State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China; 4) Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.

   Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of the 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 remains undiagnosed. Here we applied whole genome sequencing (WGS) to 50 patients with severe ID and their unaffected parents. All patients were negative after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, de novo SNVs affecting the coding region provided a conclusive genetic cause in 13 patients and a possible cause for another 8 patients. In addition, we identified 7 clinically relevant de novo CNVs as well as one recessively inherited compound heterozygous CNV. These CNVs included single exon and intraexonic deletions of known ID genes as well as interchromosomal duplications. Local realignment of sequence reads allowed the mapping of most of these CNVs at single nucleotide resolution level and provided positional information for duplicated sequences. These results show that de novo mutations and CNVs affecting the coding region are the 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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