1. Genetics of agenesis/hypoplasia of the uterus and vagina: narrowing down the number of candidate genes for Mayer-Rokitansky-Küster-Hauser Syndrome
- Author
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John A. Capra, Hugh S. Taylor, Sasha Mikhael, Madison Morton, Michael J. Friez, Amy C. Lossie, Lynn P. Chorich, Kerlene Berwick Tam, Souhrid Mukherjee, John A. Phillips, Lawrence C. Layman, Hyung-Goo Kim, James R. Knight, and Sonal Dugar
- Subjects
Male ,Candidate gene ,46, XX Disorders of Sex Development ,Translocation Breakpoint ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Article ,Congenital Abnormalities ,03 medical and health sciences ,symbols.namesake ,Mice ,Exome Sequencing ,Genetics ,Animals ,Humans ,Gene ,Mullerian Ducts ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,Sanger sequencing ,0303 health sciences ,030305 genetics & heredity ,Breakpoint ,Uterus ,Genetic Variation ,Human genetics ,Vagina ,symbols ,Female - 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.
- Published
- 2020