Lacey S Williams1, Durkadin Demir Eksi2, Yiping Shen3, Amy C Lossie4, Lynn P Chorich1, Megan E Sullivan1, John A Phillips5, Munire Erman6, Hyung-Goo Kim1, Ozgul M Alper2, Lawrence C Layman7. 1. Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia. 2. Department of Medical Biology and Genetics, Akdeniz University Faculty of Medicine, Antalya, Turkey. 3. Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts; Department of Pathology, Harvard Medical School, Boston, Massachusetts; Guangxi Maternal and Child Health Hospital, Nanning, People's Republic of China; Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. 4. Beautiful You MRKH Foundation, Silver Spring, Maryland. 5. Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee. 6. Department of Obstetrics and Gynecology, Akdeniz University Faculty of Medicine, Antalya, Turkey. 7. Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia. Electronic address: lalayman@augusta.edu.
Abstract
OBJECTIVE: To study the genetic cause of Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). Although a few candidate genes and genomic domains for have been reported for MRKH, the genetic underpinnings remain largely unknown. Some of the top candidate genes are WNT4, HNF1B, and LHX1. The goals of this study were to: 1) determine the prevalence of WNT4, HNF1B, and LHX1 point mutations, as well as new copy number variants (CNVs) in people with MRKH; and 2) identify and characterize MRKH cohorts. DESIGN: Laboratory- and community-based study. SETTING: Academic medical centers. PATIENT(S): A total of 147 MRKH probands and available family members. INTERVENTIONS(S): DNA sequencing of WNT4, HNF1B, and LHX1 in 100 MRKH patients, chromosomal microarray analysis in 31 North American MRKH patients, and characterization and sample collection of 147 North American and Turkish MRKH probands and their families. MAIN OUTCOME MEASURE(S): DNA sequence variants and CNVs; pedigree structural analysis. RESULT(S): We report finding CNVs in 6/31 people (∼19%) with MRKH, but no point mutations or small indels in WNT4, HNF1B, or LHX1 in 100 MRKH patients. Our MRKH families included 43 quads, 26 trios, and 30 duos. Of our MRKH probands, 87/147 (59%) had MRKH type 1 and 60/147 (41%) had type 2 with additional anomalies. CONCLUSION(S): Although the prevalence of WNT4, HNF1B, and LHX1 point mutations is low in people with MRKH, the prevalence of CNVs was ∼19%. Further analysis of our large familial cohort of patients will facilitate gene discovery to better understand the complex etiology of MRKH.
OBJECTIVE: To study the genetic cause of Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). Although a few candidate genes and genomic domains for have been reported for MRKH, the genetic underpinnings remain largely unknown. Some of the top candidate genes are WNT4, HNF1B, and LHX1. The goals of this study were to: 1) determine the prevalence of WNT4, HNF1B, and LHX1 point mutations, as well as new copy number variants (CNVs) in people with MRKH; and 2) identify and characterize MRKH cohorts. DESIGN: Laboratory- and community-based study. SETTING: Academic medical centers. PATIENT(S): A total of 147 MRKH probands and available family members. INTERVENTIONS(S): DNA sequencing of WNT4, HNF1B, and LHX1 in 100 MRKH patients, chromosomal microarray analysis in 31 North American MRKH patients, and characterization and sample collection of 147 North American and Turkish MRKH probands and their families. MAIN OUTCOME MEASURE(S): DNA sequence variants and CNVs; pedigree structural analysis. RESULT(S): We report finding CNVs in 6/31 people (∼19%) with MRKH, but no point mutations or small indels in WNT4, HNF1B, or LHX1 in 100 MRKH patients. Our MRKH families included 43 quads, 26 trios, and 30 duos. Of our MRKH probands, 87/147 (59%) had MRKH type 1 and 60/147 (41%) had type 2 with additional anomalies. CONCLUSION(S): Although the prevalence of WNT4, HNF1B, and LHX1 point mutations is low in people with MRKH, the prevalence of CNVs was ∼19%. Further analysis of our large familial cohort of patients will facilitate gene discovery to better understand the complex etiology of MRKH.
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