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.

识别自闭症谱系障碍 (ASD) 背后的遗传变异可能有助于更好地了解其潜在生物学。为了研究特定类型的复合杂合性在 ASD 中的可能作用，即缺失以及剩余等位基因上功能性核苷酸变异的发生，我们对 149 名 ASD 患者及其缺失传递父母的 550 个基因进行了测序。这种方法使我们能够识别在缺失的剩余等位基因中发生的其他序列变异。我们的主要目标是比较先证者和缺失传递父母之间删除区域的剩余等位基因的序列变异率。我们还使用组合注释依赖性缺失（CADD）评分检查了已识别变体的预测功能效果。在 13.4% 的先证者中观察到单核苷酸变异缺失共现，而父母中这一比例为 8.1%。合并的先证者序列中序列变异的累积负担（n  = 68）高于来自缺失传递父母的合并序列的负担（n  = 41，X ²  = 6.69，p  = 0.0097）。在筛选出那些预计最有害的变异后，我们在先证者中观察到了 21 个此类变异，而在其缺失传递父母中则观察到了 8 个此类变异（X ²  = 5.82，p  = 0.016）。最后，这些变异所赋予的累积 CADD 评分在先证者中显着高于缺失传递父母（负担检验，β  = 0.13；p  = 1.0 × 10 ^{− 5}）。我们的研究结果表明，当前研究中描述的复合杂合性可能是解释具有已知 ASD 致病性的 CNV 的可变外显率的几种机制之一。