title: Mutations in WNT9B are associated with Mayer-Rokitansky-Küster-Hauser syndrome.
abstract: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a well-known malformation pattern of the Müllerian ducts (MDs) characterized by congenital absence of the uterus and vagina. To date, most cases remain unexplained at molecular level. As female Wnt9b-/- mice show a MRKHS-like phenotype, WNT9B has emerged as a promising candidate gene for this disease. We performed retrospective sequence analyses of WNT9B in 226 female patients with disorders of the MDs, including 109 patients with MRKHS, as well as in 135 controls. One nonsense mutation and five likely pathogenic missense mutations were detected in WNT9B. Five of these mutations were found in cases with MRKHS accounting for 4.6% of the patients with this phenotype. No pathogenic mutations were detected in the control group (p = 0.017). Interestingly, all of the MRKHS patients with a WNT9B mutation were classified as MRKHS type 1, representing 8.5% of the cases from this subgroup. In previous studies, two of the patients with a WNT9B mutation were found to carry either an additional deletion of LHX1 or a missense mutation in TBX6. We conclude that mutations in WNT9B were frequently associated with MRKHS in our cohort and some cases may be explained by a digenic disease model.
authors.affiliation: Institute of Human Genetics, University Hospital of Münster, Münster, Germany.
authors.forename: D E J
authors.initials: DE
authors.lastname: Waschk
authors.affiliation: Institute of Human Genetics, University Hospital of Münster, Münster, Germany.
authors.forename: A-C
authors.initials: AC
authors.lastname: Tewes
authors.affiliation: Department of Gynecology and Obstetrics, Evangelisches Krankenhaus Köln-Weyertal, Köln, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Römer
authors.affiliation: Department of Gynecology and Obstetrics, Agaplesion Bethesda Krankenhaus, Wuppertal, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hucke
authors.affiliation: Division of Gynecology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Kapczuk
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital of Hannover, Hannover, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schippert
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital of Hannover, Hannover, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Hillemanns
authors.affiliation: Institute of Human Genetics, University Hospital of Münster, Münster, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Wieacker
authors.affiliation: Institute of Human Genetics, University Hospital of Münster, Münster, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ledig
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000235:genetics*; D001483:Base Sequence; D018389:Codon, Nonsense; D000013:Congenital Abnormalities / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009095:Mullerian Ducts / Q000002:abnormalities*; D009154:Mutation; D020125:Mutation, Missense; D012189:Retrospective Studies; D013577:Syndrome; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C449090:WNT9B protein, human; D051153:Wnt Proteins
keywords: MRKHS; Mayer-Rokitansky-Küster-Hauser syndrome; Müllerian duct anomalies; WNT9B; mutation