Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders

Tychele N. Turner, Amy B. Wilfert, Trygve E. Bakken, Raphael A. Bernier, Micah R. Pepper, Zhancheng Zhang, Rebecca I. Torene, Kyle Retterer, Evan E. Eichler

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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.

Original languageEnglish
Pages (from-to)1274-1285
Number of pages12
JournalAmerican journal of human genetics
Issue number6
StatePublished - Dec 5 2019


  • X chromosome
  • autism
  • female protective effect
  • intellectual disability
  • neurodevelopmental disorder
  • sex bias


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