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

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.