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

Abstract

Objective To study the genetic cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. 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 Patients 147 MRKH probands and available family members Interventions DNA sequencing of WNT4, HNF1B, and LHX1 in 100 MRKH patients; chromosomal microarray analysis in 31 North American MRKH patients; and ascertainment 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 Results We report finding CNVs in 6/31 (~19%) people 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. Conclusions Although the prevalence of WNT4, HNF1B, and LHX1 point mutations is low in people with MRKH, the prevalence of CNVs was about 19%. Further analysis of our large familial cohort of patients will facilitate gene discovery to better understand the complex etiology of MRKH.

Long‐term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis

“…Twenty-seven patients were analysed during the 2010s by targeted massively parallel sequencing. An amplicon-based capture panel was designed against exonic regions of 63 genes, including 43 genes already associated with human DSDs and 20 candidate genes involved in gonadal determination pathways or with a DSD phenotype in rats 1,[11][12][13][14][15][16][17][18] (see Appendix 2). Capture of the target sequences was performed using a custom Sure Select Target Enrichment System Kit (Agilent).…”

Two Distinctively Rare Syndromes in a Case of Primary Amenorrhea: 18p Deletion and Mayer–Rokitansky–Kuster–Hauser Syndromes

“…10,11 Large cohorts of familial MRKH have been reported by Williams et al analysis of which may help point the causative gene in the etiology of MRKH. 12 MRKH syndrome is classified as type 1 (isolated) and type 2 (MURCS association: Müllerian duct aplasia-renal agenesis-cervicothoracic somite dysplasia). 13 Type 2 MRKH (56%) is more common than type 1 MRKH.…”

Copy number variation and regions of homozygosity analysis in patients with MÜLLERIAN aplasia

“…Approximately 7–10% of women have uterovaginal anomalies [ 1 ], but perhaps the most severe is Müllerian aplasia, which is also known as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome—the name patients prefer [ 2 ]. These patients have congenital absence of the uterus and vagina (type I; MIM# 277000), or they may also have associated anomalies such as renal agenesis, skeletal abnormalities, cardiac anomalies, or deafness (type II; MIM# 601076) [ 3 ].…”

“…There is evidence for genetic transmission, as there are some families with more than one affected MRKH individual [ 6 , 7 ]. In our recent characterization of both North American and Turkish families ( n = 147 probands), no family had more than one affected individual, but some had another person with one or more of the associated anomalies [ 2 ]. Vertical transmission is challenging to confirm unless the MRKH woman conceive with IVF and use a gestational carrier.…”