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

Human Genetics (2021)Cite this article

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.

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Acknowledgements

This study was funded by NICHD 1R01 HD092505 (LCL).

Author information

Affiliations

  1. Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Neuroscience Program, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Sasha Mikhael, Sonal Dugar, Madison Morton, Lynn P. Chorich, Kerlene Berwick Tam & Lawrence C. Layman

  2. Beautiful You MRKH Foundation, Inc., 13301 Clifton Rd, Silver Spring, MD, 20904, USA

    Amy C. Lossie

  3. Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar

    Hyung-Goo Kim

  4. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    James Knight

  5. Yale Center for Genome Analysis, Yale University, New Haven, CT, USA

    James Knight

  6. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA

    Hugh S. Taylor

  7. Department of Biological Sciences, Center for Structural Biology, Vanderbilt University, Nashville, TN, 37232, USA

    Souhrid Mukherjee & John A. Capra

  8. Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA

    John A. Phillips III

  9. Greenwood Genetic Center, 106 Gregor Mendel Circle, Greenwood, SC, 29646, USA

    Michael Friez

  10. Department of Neuroscience and Regenerative Medicine, Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Lawrence C. Layman

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  1. Sasha Mikhael
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  2. Sonal Dugar
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  3. Madison Morton
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  4. Lynn P. Chorich
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  6. Amy C. Lossie
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  7. Hyung-Goo Kim
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  8. James Knight
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  9. Hugh S. Taylor
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  10. Souhrid Mukherjee
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  11. John A. Capra
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  12. John A. Phillips III
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  13. Michael Friez
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  14. Lawrence C. Layman
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Correspondence to Sasha Mikhael or Lawrence C. Layman.

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Mikhael, S., Dugar, S., Morton, M. et al. Genetics of agenesis/hypoplasia of the uterus and vagina: narrowing down the number of candidate genes for Mayer–Rokitansky–Küster–Hauser Syndrome. Hum Genet (2021). https://doi.org/10.1007/s00439-020-02239-y

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