Sasha Mikhael1, Sonal Dugar2, Madison Morton2, Lynn P Chorich2, Kerlene Berwick Tam2, Amy C Lossie3, Hyung-Goo Kim4, James Knight5,6, Hugh S Taylor7, Souhrid Mukherjee8, John A Capra8, John A Phillips9, Michael Friez10, Lawrence C Layman11,12. 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. smikhael@augusta.edu. 2. Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Neuroscience Program, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA. 3. Beautiful You MRKH Foundation, Inc., 13301 Clifton Rd, Silver Spring, MD, 20904, USA. 4. Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar. 5. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. 6. Yale Center for Genome Analysis, Yale University, New Haven, CT, USA. 7. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA. 8. Department of Biological Sciences, Center for Structural Biology, Vanderbilt University, Nashville, TN, 37232, USA. 9. Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA. 10. Greenwood Genetic Center, 106 Gregor Mendel Circle, Greenwood, SC, 29646, USA. 11. Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Neuroscience Program, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA. lalayman@augusta.edu. 12. Department of Neuroscience and Regenerative Medicine, Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA. lalayman@augusta.edu.
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.
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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