While genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ∼8,825 sequenced parent-child trios (n ∼26,475 individuals) and identify 54 genes with a DNM enrichment in males (n = 18), females (n = 17), or overlapping in both the male and female subsets (n = 19). A replication cohort of 18,778 sequenced parent-child trios (n = 56,334 individuals) confirms 25 genes (n = 3 in males, n = 7 in females, n = 15 in both male and female subsets). As expected, we observe significant enrichment on the X chromosome for females but also find autosomal genes with potential sex bias (females, CDK13, ITPR1; males, CHD8, MBD5, SYNGAP1); 6.5% of females harbor a DNM in a female-enriched gene, whereas 2.7% of males have a DNM in a male-enriched gene. Sex-biased genes are enriched in transcriptional processes and chromatin binding, primarily reside in the nucleus of cells, and have brain expression. By downsampling, we find that DNM gene discovery is greatest when studying affected females. Finally, directly comparing de novo allele counts in NDD-affected males and females identifies one replicated genome-wide significant gene (DDX3X) with locus-specific enrichment in females. Our sex-based DNM enrichment analysis identifies candidate NDD genes differentially affecting males and females and indicates that the study of females with NDDs leads to greater gene discovery consistent with the female-protective effect.

中文翻译：

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基于性别的神经发育障碍新生变异分析。


虽然在患有神经发育障碍 (NDD) 的儿童中发现了具有过量从头突变 (DNM) 的基因，但很少有研究关注 DNM 模式，其中对受影响儿童的性别进行单独检查。我们考虑了〜8,825个已测序的亲子三人组（n〜26,475个个体），并鉴定了男性（n = 18）、女性（n = 17）中具有DNM富集的54个基因，或者在男性和女性子集中重叠（n = 19）。由 18,778 个已测序的亲子三人组（n = 56,334 人）组成的复制队列确认了 25 个基因（男性 n = 3 个，女性 n = 7 个，男性和女性子集中 n = 15 个）。正如预期的那样，我们观察到女性 X 染色体显着富集，但也发现了具有潜在性别偏见的常染色体基因（女性，CDK13、ITPR1；男性，CHD8、MBD5、SYNGAP1）； 6.5% 的女性在富含女性的基因中含有 DNM，而 2.7% 的男性在富含男性的基因中含有 DNM。性别偏见基因在转录过程和染色质结合中丰富，主要存在于细胞核中，并在大脑中表达。通过下采样，我们发现在研究受影响的女性时，DNM 基因发现最为明显。最后，直接比较受 NDD 影响的男性和女性的从头等位基因计数，确定了一个复制的全基因组重要基因 (DDX3X)，在女性中具有位点特异性富集。我们基于性别的 DNM 富集分析确定了对男性和女性有不同影响的候选 NDD 基因，并表明对患有 NDD 的女性的研究导致了与女性保护作用一致的更多基因发现。