Strong Association of De Novo Copy Number Mutations with Autism

TLDR

The study tested whether de novo copy number variations are associated with autism spectrum disorders. The authors used comparative genomic hybridization on patient and control DNA, followed by higher‑resolution CGH, paternity testing, cytogenetics, FISH, and microsatellite genotyping to validate de novo CNVs. De novo CNVs were significantly associated with autism (P = 0.0005), occurring in 10 % of sporadic cases, 3 % of families with an affected relative, and 1 % of controls, and these small, heterogeneous variants—including single‑gene mutations—demonstrate that germline de novo mutations are a major risk factor for ASD.

Abstract

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.