Written by: Stephen Hsu
Primary Source: Information Processing
The paper below describes rare de novo mutations which cause severe intellectual disability. See also Structural genomic variants (CNVs) affect cognition.
By the principle of continuity, I suspect that rare variants of smaller negative effect on cognitive ability also exist. These alleles, although harder to detect, would account for part of the observed population variation in the normal range. As discussed in an earlier post (Common variants vs mutational load), these are likely responsible for additional heritability not included in the h2 ~ 0.5 due to common variants estimated from GCTA.
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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