@article{3076279,
    title = "Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome",
    author = "Chen, N. and Zhao, S. and Jolly, A. and Wang, L. and Pan, H. and Yuan, J. and Chen, S. and Koch, A. and Ma, C. and Tian, W. and Jia, Z. and Kang, J. and Zhao, L. and Qin, C. and Fan, X. and Rall, K. and Coban-Akdemir, Z. and Chen, Z. and Jhangiani, S. and Liang, Z. and Niu, Y. and Li, X. and Yan, Z. and Wu, Y. and Dong, S. and Song, C. and Qiu, G. and Zhang, S. and Liu, P. and Posey, J.E. and Zhang, F. and Luo, G. and Wu, Z. and Zhang, T.J. and Wu, N. and Wang, S. and Liu, J. and Liu, S. and Zuo, Y. and Liu, G. and Yu, C. and Liu, L. and Shao, J. and Zhao, H. and Wang, H. and Liu, B. and Cheng, X. and Lin, J. and Du, H. and Li, Y. and Song, S. and Xie, Z. and Zhao, Z. and Zhao, Z. and Zheng, Z. and Huang, Y. and Su, J. and Zhang, J. and Chen, E.Y. and Rouskas, K. and Glentis, S. and Bacopoulou, F. and Deligeoroglou, E. and Chrousos, G. and Lyonnet, S. and Polak, M. and Rosenberg, C. and Dingeldein, I. and Bonilla, X. and Borel, C. and Gibbs, R.A. and Dietrich, J.E. and Dimas, A.S. and Antonarakis, S.E. and Brucker, S.Y. and Lupski, J.R. and Zhu, L. and Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study group",
    journal = "American Journal of Human Genetics",
    year = "2021",
    volume = "108",
    number = "2",
    pages = "337-345",
    publisher = "Cell Press",
    issn = "0002-9297, 1537-6605",
    doi = "10.1016/j.ajhg.2020.12.014",
    keywords = "bone morphogenetic protein 4;  homeobox protein Hox-A10;  osteogenic protein 1;  transcription factor EMX2;  transcription factor PAX8;  Wnt9b protein;  BMP4 protein, human;  BMP7 protein, human;  bone morphogenetic protein 4;  empty spiracles homeobox proteins;  homeodomain protein;  HOXA10 protein, human;  osteogenic protein 1;  PAX8 protein, human;  T box transcription factor;  TBX6 protein, human;  transcription factor;  transcription factor PAX8;  Wnt protein;  WNT9B protein, human, Article;  BMP4 gene;  BMP7 gene;  Chinese;  congenital hypothyroidism;  embryo development;  EMX2 gene;  essential gene;  ethnicity;  Europe;  female genital system;  follow up;  gene;  gene disruption;  gene replication;  genetic variability;  HOXA10 gene;  human;  loss of function mutation;  Muellerian duct;  North America;  paternal inheritance;  pathogenesis;  PAX8 gene;  priority journal;  Rokitansky syndrome;  South America;  TBX6 gene;  whole exome sequencing;  WNT9B gene;  wolffian duct;  adult;  congenital disorder;  disorder of sex development;  female;  genetic association study;  genetics;  growth, development and aging;  Muellerian duct;  mutation;  penetrance;  pleiotropy;  stop codon;  wolffian duct, 46, XX Disorders of Sex Development;  Adult;  Bone Morphogenetic Protein 4;  Bone Morphogenetic Protein 7;  Codon, Nonsense;  Congenital Abnormalities;  Female;  Genetic Association Studies;  Genetic Pleiotropy;  Homeobox A10 Proteins;  Homeodomain Proteins;  Humans;  Mullerian Ducts;  Mutation;  Paternal Inheritance;  PAX8 Transcription Factor;  Penetrance;  T-Box Domain Proteins;  Transcription Factors;  Wnt Proteins;  Wolffian Ducts",
    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. © 2020 American Society of Human Genetics"
}