Three novel mutations in the PORCN gene underlying focal dermal hypoplasia.

Focal dermal hypoplasia (FDH) is an X-linked dominant disorder characterized by patchy dermal hypoplasia with digital, ocular and dental abnormalities. Very recently, mutations in the PORCN gene were demonstrated to cause FDH. Here, we described three unrelated Thai girls who were sporadic cases of FDH. One of them had unilateral athelia, which has never been described in FDH. Mutation analysis by polymerase chain reaction sequencing the entire coding regions of PORCN successfully revealed three potentially pathogenic mutations, c.373+1G>A, c.737_738insA and c.1094G>A (p.R365Q). One was found in each of three patients. In addition, another sequence variant c.682C>T (p.R228C) with an inconclusive role was found in one patient and her unaffected mother. The two missense mutations were not detected in at least 100 ethnic-matched control chromosomes, and all four mutations had never been previously described. X chromosome inactivation studies showed random patterns in all of them. This study demonstrates that PORCN is the gene responsible for FDH across different populations and extends the total number of confirmed mutations to 26.

A mutation of the p63 gene in non-syndromic cleft lip.

Mutations in the p63 gene (TP63) underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate (CL/P). We investigated whether p63 mutations also result in non-syndromic CL/P. Specifically, we performed mutation analysis of the 16 exons of the p63 gene for 100 Thai patients with non-syndromic CL/P. In total, 21 variant sites were identified. All were single nucleotide changes, with six in coding regions, including three novel non-synonymous changes: S90L, R313G, and D564H. The R313G was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, its occurrence in a functionally important domain, its predicted damaging function, its de novo occurrence, and its absence in 500 control individuals. Our data strongly suggest, for the first time, a causative role of a heterozygous mutation in the p63 gene in non-syndromic CL/P, highlighting the wide phenotypic spectrum of p63 gene mutations.