TY - JOUR
TI - Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome
AU - Chen, N.
AU - Zhao, S.
AU - Jolly, A.
AU - Wang, L.
AU - Pan, H.
AU - Yuan, J.
AU - Chen, S.
AU - Koch, A.
AU - Ma, C.
AU - Tian, W.
AU - Jia, Z.
AU - Kang, J.
AU - Zhao, L.
AU - Qin, C.
AU - Fan, X.
AU - Rall, K.
AU - Coban-Akdemir, Z.
AU - Chen, Z.
AU - Jhangiani, S.
AU - Liang, Z.
AU - Niu, Y.
AU - Li, X.
AU - Yan, Z.
AU - Wu, Y.
AU - Dong, S.
AU - Song, C.
AU - Qiu, G.
AU - Zhang, S.
AU - Liu, P.
AU - Posey, J.E.
AU - Zhang, F.
AU - Luo, G.
AU - Wu, Z.
AU - Zhang, T.J.
AU - Wu, N.
AU - Wang, S.
AU - Liu, J.
AU - Liu, S.
AU - Zuo, Y.
AU - Liu, G.
AU - Yu, C.
AU - Liu, L.
AU - Shao, J.
AU - Zhao, H.
AU - Wang, H.
AU - Liu, B.
AU - Cheng, X.
AU - Lin, J.
AU - Du, H.
AU - Li, Y.
AU - Song, S.
AU - Xie, Z.
AU - Zhao, Z.
AU - Zhao, Z.
AU - Zheng, Z.
AU - Huang, Y.
AU - Su, J.
AU - Zhang, J.
AU - Chen, E.Y.
AU - Rouskas, K.
AU - Glentis, S.
AU - Bacopoulou, F.
AU - Deligeoroglou, E.
AU - Chrousos, G.
AU - Lyonnet, S.
AU - Polak, M.
AU - Rosenberg, C.
AU - Dingeldein, I.
AU - Bonilla, X.
AU - Borel, C.
AU - Gibbs, R.A.
AU - Dietrich, J.E.
AU - Dimas, A.S.
AU - Antonarakis, S.E.
AU - Brucker, S.Y.
AU - Lupski, J.R.
AU - Zhu, L.
AU - Deciphering Disorders Involving Scoliosis
AU - COmorbidities (DISCO) study group
JO - American Journal of Human Genetics
PY - 2021
VL - 108
TODO - 2
SP - 337-345
PB - Cell Press
SN - 0002-9297, 1537-6605
TODO - 10.1016/j.ajhg.2020.12.014
TODO - 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
TODO - 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
ER -