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Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families.

ABSTRACT: 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.Laboratory- and community-based study.Academic medical centers.A total of 147 MRKH probands and available family members.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.DNA sequence variants and CNVs; pedigree structural analysis.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.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.

SUBMITTER: Williams LS

PROVIDER: S-EPMC5770980 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families.

Williams Lacey S LS Demir Eksi Durkadin D Shen Yiping Y Lossie Amy C AC Chorich Lynn P LP Sullivan Megan E ME Phillips John A JA Erman Munire M Kim Hyung-Goo HG Alper Ozgul M OM Layman Lawrence C LC

Fertility and sterility 20170607 1

<h4>Objective</h4>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 cohort ...[more]

PMID: 28600106

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Project description:BACKGROUND:Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as Müllerian aplasia, is a congenital disorder characterized by aplasia of the uterus and upper part of the vagina in females with normal secondary sex characteristics and a normal female karyotype (46,XX). MAIN BODY:The diagnosis is often made during adolescence following investigations for primary amenorrhea and has an estimated prevalence of 1 in 5000 live female births. MRKH syndrome is classified as type I (isolated uterovaginal aplasia) or type II (associated with extragenital manifestations). Extragenital anomalies typically include renal, skeletal, ear, or cardiac malformations. The etiology of MRKH syndrome still remains elusive, however increasing reports of familial clustering point towards genetic causes and the use of various genomic techniques has allowed the identification of promising recurrent genetic abnormalities in some patients. The psychosexual impact of having MRKH syndrome should not be underestimated and the clinical care foremost involves thorough counselling and support in careful dialogue with the patient. Vaginal agenesis therapy is available for mature patients following therapeutical counselling and education with non-invasive vaginal dilations recommended as first-line therapy or by surgery. MRKH syndrome involves absolute uterine factor infertility and until recently, the only option for the patients to achieve biological motherhood was through gestational surrogacy, which is prohibited in most countries. However, the successful clinical trial of uterus transplantation (UTx) by a Swedish team followed by the first live-birth in September, 2014 in Gothenburg, proofed the first available fertility treatment in MRKH syndrome and UTx is now being performed in other countries around the world allowing women with MRKH syndrome to carry their own child and achieve biological motherhood. CONCLUSION:Several advances in research across multiple disciplines have been made in the recent years and this kaleidoscopic review provides a current status of various key aspects in MRKH syndrome and provides perspectives for future research and improved clinical care.

Dataset Information

Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families.

Publications

Genetic analysis of Mayer-Rokitansky-Kuster-Hauser syndrome in a large cohort of families.

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