Genetics of agenesis/hypoplasia of the uterus and vagina: narrowing down the number of candidate genes for Mayer–Rokitansky–Küster–Hauser Syndrome

Sasha Mikhael, Sonal Dugar, Madison Morton, Lynn P. Chorich, Kerlene Berwick Tam, Amy C. Lossie, Hyung Goo Kim, James Knight, Hugh S. Taylor, Souhrid Mukherjee, John A. Capra, John A. Phillips, Michael Friez, Lawrence C. Layman

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome consists of congenital absence of the uterus and vagina and is often associated with renal, skeletal, cardiac, and auditory defects. The genetic basis is largely unknown except for rare variants in several genes. Many candidate genes have been suggested by mouse models and human studies. The purpose of this study was to narrow down the number of candidate genes. Methods: Whole exome sequencing was performed on 111 unrelated individuals with MRKH; variant analysis focused on 72 genes suggested by mouse models, human studies of physiological candidates, or located near translocation breakpoints in t(3;16). Candidate variants (CV) predicted to be deleterious were confirmed by Sanger sequencing. Results: Sanger sequencing verified 54 heterozygous CV from genes identified through mouse (13 CV in 6 genes), human (22 CV in seven genes), and translocation breakpoint (19 CV in 11 genes) studies. Twelve patients had ≥ 2 CVs, including four patients with two variants in the same gene. One likely digenic combination of LAMC1 and MMP14 was identified. Conclusion: We narrowed 72 candidate genes to 10 genes that appear more likely implicated. These candidate genes will require further investigation to elucidate their role in the development of MRKH.

Original languageEnglish (US)
Pages (from-to)667-680
Number of pages14
JournalHuman Genetics
Volume140
Issue number4
DOIs
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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