Evaluating the impact of compound heterozygosity involving microdeletions and sequence-level variants: findings in autism

Compound heterozygous events involving a chromosome deletion and on the remaining allele a functional DNA sequence-level variant can underpin a range of medical conditions. Most large-scale genetic studies do not include a systematic analysis of such compound heterozygous deletion (DelCH) events. We developed three frameworks: i) traditional burden analysis; ii) deletion-matched burden analysis; and iii) transmission disequilibrium test (TDT), to examine the possible contribution of DelCH to clinical presentations, and report results of their implementation in 9,766 families of autistic individuals. Across the three strategies, we observed enrichment of rare DelCH events in autistic individuals at a nominal significance level for individual tests. Collectively, six genes; CFHR4, HSDL1, MYO15A, NEFH, and three olfactory receptor genes; OR1A2, OR4P2, were affected by DelCH events in at least two unrelated autistic individuals (and not in unaffected family members), while the reverse analyses identified no genes (p<2.2 x 10-16). Gene set enrichment analysis of the extended network of candidate genes showing a remarkable convergence to processes related to neurogenesis. Our findings suggest a modest role for DelCH events in ASD. The strategies described here are available via a GitHub repository, allowing the research community to examine the role of DelCH in other genome sequencing cohorts.