Mutations in <i><scp>WNT9B</scp></i> are associated with Mayer–Rokitansky–Küster–Hauser syndrome

Waschk, Daniel E.J.; Tewes, Ann‐Christin; Römer, Thomas; Hucke, J.; Kapczuk, Karina; Schippert, Cordula; Hillemanns, Peter; Wieacker, Peter; Ledig, Susanne

doi:10.1111/cge.12701

Cited by 48 publications

(39 citation statements)

References 16 publications

(29 reference statements)

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“…Therefore, there is no conclusive evidence that LHX1 variants cause MRKH. A variety of other gene variants in TBX6 (29, 30), WNT9B (31, 32), and RBM8A (30) have been described, but all reports suffer from a lack of in vitro confirmation and family studies, clouding their true role in MRKH causality at this time.…”

Section: Discussionmentioning

confidence: 99%

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

Williams

Ekşi

Shen

et al. 2017

Fertility and Sterility

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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.

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Section: Discussionmentioning

confidence: 99%

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

Williams

Ekşi

Shen

et al. 2017

Fertility and Sterility

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“…Although intensively studied, the outcomes of candidate gene analyses have generally been sparse [65]. Positive findings from molecular genetic analyses include mutations in LHX1 [41, 66], TBX6 [60, 67], RBM8A [67], and WNT9B [68, 69]. Finally, mutations in WNT4 have been reported in females with Müllerian aplasia and hyperandrogenism [26, 70, 71], although it is thought to be an entity that differs from MRKH syndrome.…”

Section: Discussionmentioning

confidence: 99%

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

et al. 2016

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BackgroundThe vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome are rare conditions. We aimed to present two cases with the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser co-occurrence from our local surgical center and through a systematic literature search detect published cases. Furthermore, we aimed to collect existing knowledge in the embryopathogenesis and genetics in order to discuss a possible link between the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome.Case presentationOur first case was a white girl delivered by caesarean section at 37 weeks of gestation; our second case was a white girl born at a gestational age of 40 weeks. A co-occurrence of vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome was diagnosed in both cases.We performed a systematic literature search in PubMed ((VACTERL) OR (VATER)) AND ((MRKH) OR (Mayer-Rokitansky-Küster-Hauser) OR (mullerian agenesis) OR (mullerian aplasia) OR (MURCS)) without limitations. A similar search was performed in Embase and the Cochrane library. We added two cases from our local center.All cases (n = 9) presented with anal atresia and renal defect. Vertebral defects were present in eight patients. Rectovestibular fistula was confirmed in seven patients. Along with the uterovaginal agenesis, fallopian tube aplasia appeared in five of nine cases and in two cases ovarian involvement also existed.ConclusionsThe co-occurrence of the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome is extremely rare. This group of patients has unusual phenotypic characteristics. The long-term outcome after treatment of defects is not well reported. A single unifying cause is not known and the etiology probably includes both genetic and non-genetic causes. We stress the importance of future studies to optimized treatment, follow-up, and etiology.

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“…13 In humans, WNT7A mutations are associated with disorders of the limbs and uterus. Recently, we showed that mutations in WNT9B (winglesstype MMTV integration site family, member 9B) can cause MRKHS 14 and variants in RBM8A (RNA-binding motif protein 8A) and TBX6 (Tbox 6) are associated with disorders of the Müllerian ducts. 15 Hoxa9 is expressed in the oviducts, Hoxa10 in the uterus, Hoxa11…”

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confidence: 99%

Array‐comparative genomic hybridization analysis in patients with Müllerian fusion anomalies

et al. 2018

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Fusion anomalies of the Müllerian ducts are associated with an increased risk for miscarriage and premature labor. In most cases polygenic-multifactorial inheritance can be assumed but autosomal-dominant inheritance with reduced penetrance and variable manifestation should be considered. We performed array-comparative genomic hybridization (CGH) analysis in a cohort of 103 patients with Müllerian fusion anomalies. In 8 patients we detected microdeletions and microduplications in chromosomal regions 17q12, 22q11.21, 9q33.1, 3q26.11 and 7q31.1. The rearrangement in 17q12 including LHX1 and HNF1β as well as in 22q11.21 have already been observed in MRKHS (Mayer-Rokitansky-Küster-Hauser syndrome). In summary, we (1) detected causative micro-rearrangements in patients with Müllerian fusion anomalies, (2) show that Müllerian fusion anomalies and MRKHS may have a common etiology, and (3) identified new candidate genes for Müllerian fusion anomalies.

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Mutations in WNT9B are associated with Mayer–Rokitansky–Küster–Hauser syndrome

Cited by 48 publications

References 16 publications

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

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

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

Array‐comparative genomic hybridization analysis in patients with Müllerian fusion anomalies

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