Rare damaging variants in the sex differences of congenital heart disease: an exome sequencing study.

BACKGROUND

Congenital heart disease (CHD) exhibits a marked male predominance in birth prevalence, yet the genetic mechanisms underlying this sex disparity remain poorly understood. This study investigates the contribution of rare damaging variants on autosomes and the X chromosome to sex differences in foetal CHD.

METHODS

Parents of foetuses with CHD were recruited for the study. Rare damaging variants were identified by analysing whole-exome sequencing data from foetus-parental trios, and their contributions to sex differences were estimated through case-control studies. Functional enrichment analysis was conducted to assess functional differences in genetic variants between sexes.

FINDINGS: 820 foetal probands with CHD were recruited, including 487 males and 333 females. We identified a significant enrichment of X-linked rare damaging variants, primarily driven by maternally inherited hemizygous variants (MIHVs) in male probands (OR = 1·84, P < 0·05), which accounted for 7·2% of male cases in our cohort. These variants were not found to be enriched in female probands. Additionally, X-linked rare damaging de novo variants (DNVs) were not enriched in either male or female probands (female probands: 1·8% versus female controls: 0·7%, P = 0·6789; no DNVs observed in males). Gene-level variant burden analysis revealed three X-linked CHD candidate genes: DCX, CACNA1F, and MAP3K15. Autosomal rare variants did not show significant differences in variant burdens between sexes. Notably, male probands showed specific functional enrichments in cilia-related pathways for autosomal recessive variants, as well as in chromatin remodelling and nervous system development pathways for autosomal DNVs.

INTERPRETATION: Male and female foetal CHD have significantly different genetic landscapes. The enrichment of X-linked rare damaging MIHVs in males provides a genetic explanation for the higher prevalence of CHD in males. This finding highlights the importance of incorporating sex-stratified approaches in clinical diagnostics and research.

FUNDING: Natural Science Foundation of China and Key research and development project of Hebei Province.