Sequence Variants in TBX6 Are Associated with Disorders of the Müllerian Ducts: An Update

Mullerian anomalies comprise the Mayer-Rokitansky-Kuster-Hauser syndrome as well as fusion defects of the mullerian 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 mullerian anomalies. Since we suggested TBX6 as a strong candidate, we performed sequential analysis of the TBX6 gene in additional 125 patients with mullerian 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 mullerian ducts in the non-Finnish European population. In summary, we present increasing evidence for association of variants in TBX6 with malformations of the mullerian ducts.