The role of rare compound heterozygous events in autism spectrum disorder

Abstract

The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X² = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X² = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10^-5). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.

Fig. 1. Different compound heterozygosity scenarios.

Scenario 1: a gene is included, partly or entirely, in a deletion. A sequence variant occurs at the remaining allele of the gene, within the boundaries of the deleted region. Scenario 2: a gene is partly included in a deletion. A sequence variant occurs at the remaining allele of the gene, but outside the boundaries of the deleted region.

Fig. 2. Schematic overview of the study.

a Identification of inherited deletions in probands. In this example, the proband inherited a deletion from the father. The deletion involves one gene (red). We prioritized inherited deletions that involved one or more genes with probable relevance to the brain. b Targeted sequencing of deleted gene(s) in each proband and his/her parent(s) who transmitted the deletion. We analyzed 102 proband–parent pairs and 47 proband–parent trios. (in this figure, only proband–parent pairs are shown). c Comparing the rate of sequence variants (*) in the pooled set of sequenced genes between probands and their deletion-transmitting parents. For our analyses, for each of the 149 families we only queried the sequence of gene(s) affected by inherited deletion(s) in that specific family.