Genetic variation and molecular profiling of congenital malformations of the female genital tract based on whole-genome sequencing  

作　　者：Jun-Jun Qiu Xing-Yu Chang Ning Zhang Luo-Pei Guo Shuai Wang Wei-Yue Gu Yi-Meng Yin Zhi-Wen Shi Ke-Qin Hua 

机构地区：[1]Obstetrics and Gynecology Hospital,Fudan University,Shanghai,200011,China [2]Data and Analysis Center for Genetic Diseases,Chigene Translational Medicine Research Center,Beijing,100032,China [3]Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases,413 Zhaozhou Road,Shanghai,200011,China [4]Translational Research Institute of Brain and Brain-Like Intelligence,School of Medicine,Shanghai Fourth People’s Hospital,Tongji University,Shanghai,200434,China

出　　处：《World Journal of Pediatrics》2024年第11期1179-1195,共17页世界儿科杂志（英文版）

基　　金：The National Key R&D Program of China(2021YFC2701400 and 2021YFC2701404).

摘　　要：Background Congenital malformations of the female genital tract(CM-FGT)are characterized by abnormal development of the fallopian tubes,uterus,and vagina,often accompanied by malformations in the urinary system,bones and hearing.However,no definitive pathogenic genes and molecular genetic causes have been identified.Methods We present the largest whole-genome sequencing study of CM-FGT to date,analyzing 590 individuals in China:95 patients,442 case–controls,and 53 familial controls.Results Among the patients,5.3% carried known CM-FGT-related variants.Pedigree and case–control analyses in two dimensions of coding and non-coding regulatory regions revealed seven novel de novo copy number variations,12 rare single-nucleotide variations,and 10 rare 3'untranslated region(UTR)mutations in genes related to CM-FGT,particularly highlighting ASH1L as a pathogenic gene.Single-cell sequencing data showed that the majority of CM-FGT-related risk genes are spatiotemporally specifically expressed early in uterus development.Conclusions In conclusion,this study identified novel variants related to CM-FGT,particularly highlighting ASH1L as a pathogenic gene.The findings provide insights into the genetic variants underlying CM-FGT,with single-cell sequencing data revealing spatiotemporal specific expression patterns of key risk genes early in uterine development.This study significantly advances the understanding of CM-FGT etiology and genetic landscape,offering new opportunities for prenatal screening.

关 键 词：Copy number variant Congenital malformations of the female genital tract Single nucleotide variants Whole-genome sequencing 

分 类 号：R394[医药卫生—医学遗传学] R71[医药卫生—基础医学]