Abstract
Congenital absence of the uterus and vagina (CAUV) is the most extreme female Müllerian duct abnormality. Several researches proposed that genetic factors contributed to this disorder, whereas the precise genetic mechanism is far from full elucidation. Here, utilizing whole-exome sequencing (WES), we identified one novel missense mutation in LHX1 (NM_005568: c.G1108A, p.A370T) in one of ten unrelated patients diagnosed with CAUV. This mutation was absent from public databases and our internal database. Through the luciferase reporter analysis, we found that the mutation could change the transcriptional activity of LHX1 and its effect on the regulation of the downstream target gene GSC, which might be associated with urogenital system development. In short, we concluded that the LHX1 may be a pathogenic gene of CAUV. Our results demonstrate the power of whole exome sequencing and gene prioritization approach as diagnostic tools in clinical practice that help make genetic diagnosis of CAUV.
Highlights
Müllerian duct abnormality (MDA) is a complex and serious female reproductive tract malformation, which bring serious physical and psychological impact on patients [1]
Through the luciferase reporter analysis, we found that the mutation could change the transcriptional activity of LHX1 and its effect on the regulation of the downstream target gene goosecoid homeobox (GSC), which might be associated with urogenital system development
By performing whole-exome sequencing, quality control statistics, strict filtering criteria and bioinformatic analysis in a cohort of Congenital absence of the uterus and vagina (CAUV) patients, we identified a novel heterozygous missense variant in the LHX1 gene (NM_005568: c.G1108A, p.A370T) in one patient
Summary
Müllerian duct abnormality (MDA) is a complex and serious female reproductive tract malformation, which bring serious physical and psychological impact on patients [1]. Congenital absence of the uterus and vagina (CAUV), known as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, is the most extreme MDA, characterized by the congenital aplasia of the uterus and the upper part of the vagina in women with normal ovaries, karyotypes and secondary sexual characteristics [2, 3]. It is the second most frequent cause of primary amenorrhea after Turner syndrome in females, and the estimated prevalence of the disease was about 1 in 4000 to 5000 female newborns [4]. What’s more, hardly any candidate genes or mutations were verified by functional analysis to enhance the understanding of how and why they influenced the development of Müllerian ducts
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