One mutation, two phenotypes: a single nonsense mutation of theCTSCgene causes two clinically distinct phenotypes

Summary Background Papillon–Lefevre syndrome (PLS; OMIM 245000) and Haim–Munk syndromes (HMS; OMIM 245010) are phenotypic variants of the same rare disease caused by mutations of the cathepsin C (CTSC) gene, and they exhibit autosomal recessive inheritance. Aims To identify diseases caused by mutations of the CTSC gene in two Hungarian patients and to perform haplotype analysis to elucidate any familial relationship between them. Methods Mutation screening and polymorphism analysis were performed by direct sequencing of the CTSC gene. Results Mutation screening of the CTSC gene from the two patients revealed the presence of the same homozygous nonsense mutation (c.748C/T; p.Arg250X). However, one patient exhibited the PLS phenotype and the other the HMS phenotype. Although these patients were not aware that they were related, haplotype analysis, especially the genotypes of the rs217116 and the rs217115 polymorphisms, clearly indicated that the patients carry the same haplotype, whereas the unrelated healthy controls carried several different haplotypes. Conclusions Our results demonstrate that PLS and HMS are phenotypic variants of the same disease and, additionally, exclude the presence of a putative genetic modifier factor within the CTSC gene that is responsible for the development of the two phenotypes. We suggest that this putative genetic modifier factor is located outside the CTSC gene, or alternatively, that the development of the different phenotypes is the consequence of different environmental or lifestyle factors.