Analysis of WNT9B mutations in Chinese women with Mayer–Rokitansky–Küster–Hauser syndrome

Wang, Man; Li, Yan; Ma, Wenqing; Li, Haixia; He, Fan; Pu, Demin; Su, Tiefen; Wang, Shixuan

doi:10.1016/j.rbmo.2013.09.022

Cited by 31 publications

(30 citation statements)

References 28 publications

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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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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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“…We failed to replicate the 7 following previously reported variants: rs16826648 [10], c.697G>A [15] and c.483C>T [8] in WNT4; c.342C>T [10] and c.861G>A [8] in WNT7A; c.113C>G [18] in HOXA11; and c.791G>C [25] in LHX1. The remaining 5 variants (rs3749319 [10] and rs3762719 [10] in WNT7A; C.170A>G [17] in HOXA10; rs2070072 [14] in GALT; and c.*158C>T [16] in WNT9B) were detected, but there were no significant differences in the frequencies of these genotypes or alleles between the cases and controls in this Chinese cohort (Table 2). These discrepancies may be due to differences among the study populations assessed and genetic heterogeneity, which has been observed in previous studies, especially in studies of monozygotic twins [26, 27].…”

Section: Discussionmentioning

confidence: 82%

Associations of Polymorphisms in WNT9B and PBX1 with Mayer-Rokitansky-Küster-Hauser Syndrome in Chinese Han

Wang

et al. 2015

PLoS ONE

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BackgroundMayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare syndrome that is characterized by congenital aplasia of the uterus and the upper portion (2/3) of the vagina. Previous attempts to identify causal mutations of MRKH syndrome have primarily resulted in negative outcomes. We investigated whether these reported variants are associated with MRKH syndrome (types I and II) in a relatively large sample size of Chinese Han patients, and whether any gene-gene epistatic interactions exist among these variants.MethodsThis study included 182 unrelated Chinese women with MRKH syndrome (155 with type I and 27 with type II) and 228 randomized female controls. Seventeen candidate loci in the AMH, PBX1, WNT4, WNT7A, WNT9B, HOXA10, HOXA11, LHXA1 and GALT genes were genotyped using the Sequenom MassARRAY iPLEX platform. Single-marker association, additive effects and multifactor interactions were investigated.ResultsThe gene frequency distributions of MRKH type 1 and type 2 were similar. Rs34072914 in WNT9B was found to be associated with MRKH syndrome (P = 0.024, OR = 2.65, 95%CI = 1.14–6.17). The dominant models of rs34072914 and rs2275558 in WNT9B and PBX1, respectively, were significantly associated with MRKH syndrome risk in the Chinese Han patients. Additive gene-gene interaction analyses indicated a significant synergetic interaction between WNT9B and PBX1 (RERI = 1.397, AP = 0.493, SI = 4.204). Multifactor dimensionality reduction (MDR) analysis revealed novel dimensional epistatic four-gene effects (AMH, PBX1, WNT7A and WNT9B) in MRKH syndrome.ConclusionsThis association study successfully identified two susceptibility SNPs (WNT9B and PBX1) associated with MRKH syndrome risk, both separately and interactively. The discovery of a four-gene epistatic effect (AMH, PBX1, WNT7A and WNT9B) in MRKH syndrome provides novel information for the elucidation of the genetic mechanism underlying the etiology of MRKH syndrome.

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“…Mutations in WNT4 are associated with MRKHS and androgen excess. Furthermore, the studies of Wang et al [2014] and Waschk et al [2016] showed also an association between mutations [Morcel et al, 2007]. This interval contains the TBX6 gene (OMIM 602427) encoding a sequence-specific DNA transcription factor, which belongs to the T-box gene family [Wilson and Conlon, 2002].…”

Section: Discussionmentioning

confidence: 99%

“…It is known that WNT4 mutations are causative for a subgroup of MRKHS with signs of hyperandrogenism [Biason-Lauber et al, 2004]. Recently, the studies of Wang et al [2014] and Waschk et al [2016] showed an association between mutations in WNT9B and disorders of the müllerian ducts.…”

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confidence: 99%

Sequence Variants in <b><i>TBX6</i></b> Are Associated with Disorders of the Müllerian Ducts: An Update

Tewes¹,

Hucke²,

Römer³

et al. 2019

Sex Dev

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Müllerian anomalies comprise the Mayer-Rokitansky-Küster-Hauser syndrome as well as fusion defects of the müllerian ducts. Recurrent micro-aberrations like deletions in 16p11.2 encompassing TBX6 were found to be causative in these patients. TBX6 encodes a transcription factor which plays a role in paraxial mesoderm differentiation/specification. In previous studies, we and other groups found possibly pathogenic variants in TBX6 in patients with müllerian anomalies. Since we suggested TBX6 as a strong candidate, we performed sequential analysis of the TBX6 gene in additional 125 patients with müllerian anomalies, and 2 possibly pathogenic missense variants and 1 nonsense substitution in TBX6 in 4/125 patients were found. The missense variant c.484G>A, which we have described in a previous study, was reidentified but with no higher frequency as in our controls. We detected 3 possibly pathogenic variants in TBX6 and could show that the variant c.484G>A is not causative for disorders of the müllerian ducts in the non-Finnish European population. In summary, we present increasing evidence for association of variants in TBX6 with malformations of the müllerian ducts.

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Analysis of WNT9B mutations in Chinese women with Mayer–Rokitansky–Küster–Hauser syndrome

Cited by 31 publications

References 28 publications

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

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

Associations of Polymorphisms in WNT9B and PBX1 with Mayer-Rokitansky-Küster-Hauser Syndrome in Chinese Han

Sequence Variants in <b><i>TBX6</i></b> Are Associated with Disorders of the Müllerian Ducts: An Update

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