Rare damaging variants in the sex differences of congenital heart disease: an exome sequencing studyResearch in context
Hairui Sun,
Xiaoyan Hao,
Hankui Liu,
Siyao Zhang,
Jiancheng Han,
Ye Zhang,
Tingting Liu,
Xian Yang,
Hairui Wang,
Jiaqi Fan,
Yuxuan Guan,
Ni Peng,
Jiaoyang Xie,
Hongmei Xia,
Xueqin Ji,
Yan Xu,
Jianguo Zhang,
Jianbin Wang,
Feng Lan,
Hongjia Zhang,
Xiaoyan Gu,
Yihua He
Affiliations
Hairui Sun
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
Xiaoyan Hao
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Hankui Liu
BGI-genomics, BGI-Shenzhen, Shenzhen, 518083, China
Siyao Zhang
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Jiancheng Han
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Ye Zhang
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Tingting Liu
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Xian Yang
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Hairui Wang
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Jiaqi Fan
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Yuxuan Guan
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Ni Peng
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Jiaoyang Xie
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China
Hongmei Xia
Department of Ultrasound, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
Xueqin Ji
Department of Ultrasound, Ningxia Women's and Children's Hospital, Beijing University First Hospital (Ningxia Hui Autonomous Region Maternal and Child Health Hospital), Yinchuan, 750004, China
Yan Xu
Rizhao People's Hospital, Shandong, 276827, China
Jianguo Zhang
BGI-genomics, BGI-Shenzhen, Shenzhen, 518083, China
Jianbin Wang
School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
Feng Lan
Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China
Hongjia Zhang
Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China
Xiaoyan Gu
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China; Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China; Corresponding author. Maternal-Fetal Medicine Center in Fetal Heart Disease, Capital Medical University, Beijing Anzhen Hospital, Beijing, 100029, China.
Yihua He
Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China; Beijing Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease, Beijing, 100029, China; Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China; Corresponding author. Maternal-Fetal Medicine Center in Fetal Heart Disease, Capital Medical University, Beijing Anzhen Hospital, Beijing, 100029, China.
Summary: 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.
