Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families

Fertil Steril. 2017 Jul;108(1):145-151.e2. doi: 10.1016/j.fertnstert.2017.05.017. Epub 2017 Jun 7.

Abstract

Objective: To study the genetic cause of Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). Although a few candidate genes and genomic domains for have been reported for MRKH, the genetic underpinnings remain largely unknown. Some of the top candidate genes are WNT4, HNF1B, and LHX1. The goals of this study were to: 1) determine the prevalence of WNT4, HNF1B, and LHX1 point mutations, as well as new copy number variants (CNVs) in people with MRKH; and 2) identify and characterize MRKH cohorts.

Design: Laboratory- and community-based study.

Setting: Academic medical centers.

Patient(s): A total of 147 MRKH probands and available family members.

Interventions(s): DNA sequencing of WNT4, HNF1B, and LHX1 in 100 MRKH patients, chromosomal microarray analysis in 31 North American MRKH patients, and characterization and sample collection of 147 North American and Turkish MRKH probands and their families.

Main outcome measure(s): DNA sequence variants and CNVs; pedigree structural analysis.

Result(s): We report finding CNVs in 6/31 people (∼19%) with MRKH, but no point mutations or small indels in WNT4, HNF1B, or LHX1 in 100 MRKH patients. Our MRKH families included 43 quads, 26 trios, and 30 duos. Of our MRKH probands, 87/147 (59%) had MRKH type 1 and 60/147 (41%) had type 2 with additional anomalies.

Conclusion(s): Although the prevalence of WNT4, HNF1B, and LHX1 point mutations is low in people with MRKH, the prevalence of CNVs was ∼19%. Further analysis of our large familial cohort of patients will facilitate gene discovery to better understand the complex etiology of MRKH.

Keywords: MRKH; Müllerian aplasia; congenital absence of the uterus and vagina; gene mutation; reproductive genetics.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • 46, XX Disorders of Sex Development / epidemiology*
  • 46, XX Disorders of Sex Development / genetics*
  • Adult
  • Cohort Studies
  • Congenital Abnormalities / epidemiology*
  • Congenital Abnormalities / genetics*
  • Family
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics
  • Hepatocyte Nuclear Factor 1-beta / genetics*
  • Humans
  • Internationality
  • LIM-Homeodomain Proteins / genetics*
  • Mullerian Ducts / abnormalities*
  • Polymorphism, Single Nucleotide / genetics*
  • Prevalence
  • Risk Factors
  • Transcription Factors / genetics*
  • Wnt4 Protein / genetics*
  • Young Adult

Substances

  • Genetic Markers
  • HNF1B protein, human
  • LHX1 protein, human
  • LIM-Homeodomain Proteins
  • Transcription Factors
  • WNT4 protein, human
  • Wnt4 Protein
  • Hepatocyte Nuclear Factor 1-beta

Supplementary concepts

  • Mullerian aplasia