Journal Article

Genome sequencing identifies major causes of severe intellectual disability

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

2014

Overview

Whole-genome sequencing is used to identify genetic alterations in patients with severe intellectual disability for whom all other tests, including array and exome sequencing, returned negative results; de novo single-nucleotide and copy number variations affecting the coding region seem to be a major cause of this disorder. Gene variation in intellectual disability Intellectual disability has been shown to be linked to genetic variation but the majority of cases remain undiagnosed. This paper demonstrates the use of whole-genome sequencing to identify genetic alterations in patients with severe intellectual disability for whom all other tests, including array and exome sequencing, had returned negative results. Whole-genome sequencing of 50 patients with severe intellectual disability — and with no family history of the condition — resulted in a conclusive genetic diagnosis in 21 patients. The results suggest that de novo copy number variations and single-nucleotide variations affecting the coding region are a major cause of severe intellectual disability. 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 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 45/23 / 631/208/366 / 631/208/514/2254 / Binding sites / Causes of / Chromosomes, Human, Pair 4 - genetics / Chromosomes, Human, X - genetics / Cohort Studies / DNA Copy Number Variations - genetics / DNA sequencing / Gene Duplication - genetics / Gene mutations / Genes / Genetic aspects / Genetic diversity / Genetic variation / Genome, Human - genetics / Genomes / Guanine Nucleotide Exchange Factors - genetics / Heterogeneity / Humanities and Social Sciences / Humans / Identification and classification / Intellectual disabilities / Intellectual Disability - genetics / letter / Male / Mental retardation / Methods / multidisciplinary / Mutation / Mutation - genetics / Nucleotide sequencing / Patients / Physiological aspects / Polymorphism, Single Nucleotide - genetics / Science / Sequence Analysis, DNA