Deficiency of PORCN, a regulator of Wnt signaling, causes focal dermal hypoplasia. K.-H. Grzeschik1, D. Bornholdt1, F. Oeffner1, A. Koenig2, M. Boente3, H. Enders4, B. Fritz1, M. Hertl2, U. Grasshoff4, K. Hoefling5, V. Oji6, M. Paradisi7, C. Schuchardt8, Z. Szalai9, G. Tadini10, H. Traupe6, R. Happle2 1) Human Genetics, University of Marburg, Germany; 2) Dermatology, University of Marburg, Germany; 3) Dermatology, Hospital San Miguel de Tucumán, Argentina; 4) Human Genetics, University of Tuebingen, Germany; 5) Medical Microbiology, University of Bonn, Germany; 6) Dermatology, University of Muenster, Germany; 7) Pedatric Dermatology, IDI, Roma, Italy; 8) Klinik Pieper. St. Blasien-Menzenschwand, Germany; 9) Pediatric Dermatology, Children's Hospital, Budapest, Hungary; 10) Dermatological Science, University of Milan, Italy.

   Focal dermal hypoplasia (FDH, Goltz syndrome, MIM 305600) is an X-linked dominant, male-lethal, mostly sporadic multisystem birth defect affecting a multitude of tissues of ectodermal and mesodermal origin.
   Using a stepwise, generally applicable approach employing i) genetic mapping of FDH in rare familial cases, ii) comparative genome hybridization on custom made high resolution arrays (HR-CGH) to search sporadic cases for small deletions in candidate chromosome areas associated with this Mendelian trait, iii) point mutation analysis in genes highlighted by overlapping deletions, we identify PORCN, located in Xp11.23, as the gene mutated in FDH. Focusing the CGH analysis by independent methods, such as genetic mapping, on restricted candidate areas eliminates ambiguities which might arise from the wealth of copy number variants in the human genome unrelated to the phenotype under study. Contiguous gene deletions or stop mutations affecting PORCN result in loss of function of this putative O-acyltransferase, crucial for cellular export of Wnt signaling proteins. The defect is detectable at the cellular level. Hence, FDH is a human developmental disorder caused by deficient Wnt signal production. Extreme skewing of X-inactivation or postzygotic mosaicism reduce the deleterious consequences of mutations in female patients. Due to the severity of the PORCN deficiency in cells with active mutant X-chromosome, effects of missing neighbouring genes in contiguous deletions are covered by epistasis.