<i>WT1</i> mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations

Meacham syndrome is a rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities. We report on eight new cases of this condition, two of whom were shown to have heterozygous missense mutations in the C-terminal zinc finger domains of WT1: Arg366Cys and Arg394Trp. These data represent clinical and molecular evidence that the WT1 gene plays a central role in normal development of the diaphragm and the proepicardially derived tissues. Identification of WT1 expression in the region of coelomic mesothelium which will form the proepicardium and diaphragm provides a plausible unifying patterning defect in these cases. Interestingly, the Arg366Cys mutation has been previously reported in Denys-Drash syndrome and Arg394Trp mutation has been previously reported in both isolated Wilms tumor and Denys-Drash syndrome. This phenotypic diversity with a single mutation suggests there are other factors modulating all aspects of WT1 function during human development. If genetic modifiers of WT1 can be identified in animal models these become good candidate genes for the cases with Meacham syndrome we report on here where WT1 mutations cannot be identified.