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Perturbations of genes essential for Mullerian duct and Wolffian duct development in Mayer-Rokitansky-Kuster-Hauser syndrome.

ABSTRACT: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

SUBMITTER: Chen N

PROVIDER: S-EPMC7896104 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome.

Chen Na N Zhao Sen S Jolly Angad A Wang Lianlei L Pan Hongxin H Yuan Jian J Chen Shaoke S Koch André A Ma Congcong C Tian Weijie W Jia Ziqi Z Kang Jia J Zhao Lina L Qin Chenglu C Fan Xin X Rall Katharina K Coban-Akdemir Zeynep Z Chen Zefu Z Jhangiani Shalini S Liang Ze Z Niu Yuchen Y Li Xiaoxin X Yan Zihui Z Wu Yong Y Dong Shuangshuang S Song Chengcheng C Qiu Guixing G Zhang Shuyang S Liu Pengfei P Posey Jennifer E JE Zhang Feng F Luo Guangnan G Wu Zhihong Z Su Jianzhong J Zhang Jianguo J Chen Eugenia Y EY Rouskas Konstantinos K Glentis Stavros S Bacopoulou Flora F Deligeoroglou Efthymios E Chrousos George G Lyonnet Stanislas S Polak Michel M Rosenberg Carla C Dingeldein Irene I Bonilla Ximena X Borel Christelle C Gibbs Richard A RA Dietrich Jennifer E JE Dimas Antigone S AS Antonarakis Stylianos E SE Brucker Sara Y SY Lupski James R JR Wu Nan N Zhu Lan L

American journal of human genetics 20210201 2

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subject ...[more]

PMID: 33434492

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Project description:BackgroundMayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as Müllerian aplasia, is a congenital disorder characterized by aplasia of the uterus and upper part of the vagina in females with normal secondary sex characteristics and a normal female karyotype (46,XX).Main bodyThe diagnosis is often made during adolescence following investigations for primary amenorrhea and has an estimated prevalence of 1 in 5000 live female births. MRKH syndrome is classified as type I (isolated uterovaginal aplasia) or type II (associated with extragenital manifestations). Extragenital anomalies typically include renal, skeletal, ear, or cardiac malformations. The etiology of MRKH syndrome still remains elusive, however increasing reports of familial clustering point towards genetic causes and the use of various genomic techniques has allowed the identification of promising recurrent genetic abnormalities in some patients. The psychosexual impact of having MRKH syndrome should not be underestimated and the clinical care foremost involves thorough counselling and support in careful dialogue with the patient. Vaginal agenesis therapy is available for mature patients following therapeutical counselling and education with non-invasive vaginal dilations recommended as first-line therapy or by surgery. MRKH syndrome involves absolute uterine factor infertility and until recently, the only option for the patients to achieve biological motherhood was through gestational surrogacy, which is prohibited in most countries. However, the successful clinical trial of uterus transplantation (UTx) by a Swedish team followed by the first live-birth in September, 2014 in Gothenburg, proofed the first available fertility treatment in MRKH syndrome and UTx is now being performed in other countries around the world allowing women with MRKH syndrome to carry their own child and achieve biological motherhood.ConclusionSeveral advances in research across multiple disciplines have been made in the recent years and this kaleidoscopic review provides a current status of various key aspects in MRKH syndrome and provides perspectives for future research and improved clinical care.

Dataset Information

Perturbations of genes essential for Mullerian duct and Wolffian duct development in Mayer-Rokitansky-Kuster-Hauser syndrome.

Publications

Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome.

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