ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:2312–2320 (2007) WT1 Mutations in Meacham Syndrome Suggest a Coelomic Mesothelial Origin of the Cardiac and Diaphragmatic Malformations Mohnish Suri, 1 Peter Kelehan, 2 David O’Neill, 3 Shantala Vadeyar, 4 Judith Grant, 5 S. Faisal Ahmed, 6 John Tolmie, 7 Emma McCann, 8 Wayne Lam, 9 Shirley Smith, 10 David FitzPatrick, 9,10 Nicholas D. Hastie, 10 and William Reardon 11 * 1 Clinical Genetics Service, City Hospital, Nottingham, UK 2 Department of Pathology and Laboratory Medicine, National Maternity Hospital, Crumlin, Dublin, Ireland 3 Department of Pathology, Queen’s Medical Centre, Nottingham, UK 4 Department of Neonatal Medicine and Surgery, Queen’s Medical Centre, Nottingham, UK 5 Department of Obstetrics and Gynaecology, Manchester, UK 6 Royal Hospital For Sick Children, Yorkhill, Glasgow, UK 7 Department of Medical Genetics, Royal Hospital for Sick Children, Glasgow, UK 8 Department of Clinical Genetics, Royal Liverpool Children’s Hospital, Liverpool, UK 9 Department of Clinical Genetics, Western General Hospital, Edinburgh, UK 10 MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK 11 National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin, Ireland Received 15 June 2006; Accepted 26 May 2007 How to cite this article: Suri M, Kelehan P, O’Neill D, Vadeyar S, Grant J, Ahmed SF, Tolmie J, McCann E, Lam W, Smith S, FitzPatrick D, Hastie ND, Reardon W. 2007. WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations. Am J Med Genet Part A 143A:2312 – 2320. Meacham syndrome is a rare sporadically occurring multiple malformation syndrome characterized by male pseudoher- maphroditism 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 pro- epicardium 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. ß 2007 Wiley-Liss, Inc. Key words: Meacham syndrome; male pseudohermaphro- ditism; 46,XY sex-reversal; diaphragmatic hernia; congenital heart defect; hypoplastic left heart; WT1 INTRODUCTION The co-dependence of clinical and laboratory science has rarely been better demonstrated than through the identification of the WT1 gene in 1990 [Call et al., 1990; Gessler et al., 1990]. The clinical recognition of the WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies and Retardation) as a discrete clinical entity leading to the identifica- tion of a specific chromosome 11p deletion associ- ated with this contiguous gene deletion syndrome was central to the narrative [Miller et al., 1964; Anderson et al., 1978; Riccardi et al., 1978; Fantes et al., 1992]. Ultimately the identification of the WT1 gene sprang from investigation of patients with *Correspondence to: Dr. William Reardon, National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland. E-mail: willie.reardon@olhsc.ie DOI 10.1002/ajmg.a.31924