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

• Published in: Human genetics 2021-04, Vol.140 (4), p.667-680
• Main Authors: Mikhael, Sasha, Dugar, Sonal, Morton, Madison, Chorich, Lynn P., Tam, Kerlene Berwick, Lossie, Amy C., Kim, Hyung-Goo, Knight, James, Taylor, Hugh S., Mukherjee, Souhrid, Capra, John A., Phillips, John A., Friez, Michael, Layman, Lawrence C.
• Format: Article
• Language: English
• Subjects: 46, XX Disorders of Sex Development - genetics; 46, XX Disorders of Sex Development - pathology; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Breakpoints; Congenital Abnormalities - genetics; Congenital Abnormalities - pathology; Exome Sequencing; Female; Gene Function; Genetic Variation; Human Genetics; Humans; Hypoplasia; Metabolic Diseases; Mice; Molecular Medicine; Mullerian Ducts - abnormalities; Mullerian Ducts - pathology; Original Investigation; Translocation, Genetic; Uterus; Uterus - abnormalities; Vagina; Vagina - abnormalities
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-020-02239-y

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.