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

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. Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Na Chen, Sen Zhao, Angad Jolly, Lianlei Wang, Hongxin Pan, Jian Yuan, Shaoke Chen, André Koch, Congcong Ma, Weijie Tian, Ziqi Jia, Jia Kang, Lina Zhao, Chenglu Qin, Xin Fan, Katharina Rall, Zeynep Coban-Akdemir, Zefu Chen, Shalini Jhangiani, Ze Liang, Yuchen Niu, Xiaoxin Li, Zihui Yan, Yong Wu, Shuangshuang Dong, Chengcheng Song, Guixing Qiu, Shuyang Zhang, Pengfei Liu, Jennifer E Posey, Feng Zhang, Guangnan Luo, Zhihong Wu, Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study group, Jianzhong Su, Jianguo Zhang, Eugenia Y Chen, Konstantinos Rouskas, Stavros Glentis, Flora Bacopoulou, Efthymios Deligeoroglou, George Chrousos, Stanislas Lyonnet, Michel Polak, Carla Rosenberg, Irene Dingeldein, Ximena Bonilla, Christelle Borel, Richard A Gibbs, Jennifer E Dietrich, Antigone S Dimas, Stylianos E Antonarakis, Sara Y Brucker, James R Lupski, Nan Wu, Lan Zhu. Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome. American journal of human genetics. 2021 Feb 04;108(2):337-345

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PMID: 33434492

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