背景:女性生殖道先天性畸形(CM-FGT)的特征是输卵管发育异常,子宫,还有阴道,常伴有泌尿系统畸形,骨头和听觉然而,尚未发现明确的致病基因和分子遗传原因。
方法:我们提出了迄今为止最大的CM-FGT全基因组测序研究,分析590名中国人:95名患者,442个案例控制,和53个家族控制。
结果:在患者中,5.3%携带已知的CM-FGT相关变体。在编码和非编码调控区的两个维度上的谱系和病例对照分析揭示了七个新的从头拷贝数变异,12个罕见的单核苷酸变异,和10个罕见的3'非翻译区(UTR)突变的基因相关的CM-FGT,特别强调ASH1L作为致病基因。单细胞测序数据显示,大多数CM-FGT相关的风险基因在子宫发育早期是时空特异性表达的。
结论:结论:这项研究确定了与CM-FGT相关的新变体,特别强调ASH1L作为致病基因。这些发现提供了对CM-FGT潜在遗传变异的见解,单细胞测序数据揭示了子宫发育早期关键风险基因的时空特异性表达模式。这项研究大大推进了对CM-FGT病因和遗传景观的理解,为产前筛查提供新的机会。
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.