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

Am J Hum Genet. 2021 Feb 4;108(2):337-345. doi: 10.1016/j.ajhg.2020.12.014.


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.

Keywords: MRKHS; MRKHS, Müllerian duct; Mayer-Rokitansky-Küster-Hauser syndrome; Müllerian aplasia; PAX8; Wölffian duct.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 46, XX Disorders of Sex Development / genetics*
  • Adult
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 7 / genetics
  • Codon, Nonsense
  • Congenital Abnormalities / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Pleiotropy
  • Homeobox A10 Proteins / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Mullerian Ducts / abnormalities*
  • Mullerian Ducts / growth & development*
  • Mutation*
  • PAX8 Transcription Factor / genetics
  • Paternal Inheritance
  • Penetrance
  • T-Box Domain Proteins / genetics
  • Transcription Factors / genetics
  • Wnt Proteins / genetics
  • Wolffian Ducts / abnormalities
  • Wolffian Ducts / growth & development*


  • BMP4 protein, human
  • BMP7 protein, human
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein 7
  • Codon, Nonsense
  • Homeobox A10 Proteins
  • Homeodomain Proteins
  • PAX8 Transcription Factor
  • PAX8 protein, human
  • T-Box Domain Proteins
  • TBX6 protein, human
  • Transcription Factors
  • WNT9B protein, human
  • Wnt Proteins
  • empty spiracles homeobox proteins
  • HOXA10 protein, human

Supplementary concepts

  • Mullerian aplasia