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Background  Müllerian aplasia (MA) is a congenital disorder of the female reproductive tract with absence of uterus and vagina with paramount impact on a woman’s life. Despite intense research, no major genes have been found to explain the complex genetic etiology.    Methods and Results  We have used several genetic methods to study 112 patients with MA. aCGH identified CNVs in 8/50 patients (16%), including 16p11.2 and 17q12 deletions previously associated with MA. Subsequently, another four patients were shown to carry the ~0.53 Mb deletion in 16p11.2. More importantly, sequencing of  TBX6,  residing within 16p11.2, revealed two patients carrying a splice site mutation .  Two previously reported  TBX6  variants in exon 4 and 6 were shown to have a significantly higher frequency in patients (8% and 5%, respectively) than in controls (2% each). We also sequenced  LHX1  and found three apparently pathogenic missense variants in 5/112 patients. Altogether, we identified either CNVs or variations in  TBX6  or  LHX1  in 30/112 (26.8%) MA patients. CNVs were found in 12/112 (10.7%), patients, novel variants in  TBX6  or  LHX1  in 7/112 (6.3%), and rare variants in  TBX6  in 15/112 (13.4%) patients. Furthermore, four of our patients (4/112, 3.6%) were shown to carry variants in both  TBX6  and  LHX1  or a CNV in combination with  TBX6  variants lending support to the complex genetic etiology of MA.    Conclusions  We have identified  TBX6  as a new gene associated with MA. Our results also support the relevance of  LHX1  and CNVs in the development of this congenital malformation.

TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia