Papillon-Lefévre (PLS; OMIM 245000) and Haim-Munk syndromes (HMS; OMIM 245010), characterized by palmoplantar hyperkeratosis and periodontitis, are phenotypic variants of the same disease caused by mutations of the cathepsin C (CTSC) gene. To identify putative genetic modifying factors responsible for the development of the distinct PLS or HMS phenotypes, two Hungarian patients - suffering from different phenotypic variants (PLS and HMS) but carrying the same homozygous nonsense CTSC mutation (c.748C/T; p.Arg250X) - were investigated. To gain insights into such phenotype modifier associations, whole exome sequencing (WES) was performed for both patients and their results were compared to each other to identify any genetic modifier factor. WES revealed two putative disease modifying variants: a missense one (rs34608771) of the SH2 domain containing 4A (SH2D4A) gene encoding an adaptor protein involved in the intracellular signaling of the cystatin F, a known inhibitor of the cathepsin C protein, and another missense variant (rs55695858) of the odorant binding protein 2A (OBP2A) gene influencing the functioning of the cathepsin C protein through the glycosyltransferase 6 domain containing 1 (GLT6D1) protein. Our study contributes to the accumulating evidence describing the clinical importance of genetic phenotype modifying factors, which have high potential in the elucidation of genotype-phenotype correlations and disease prognosis.

Identification of putative genetic modifying factors influencing the development of Papillon-Lefévre or Haim-Munk syndrome phenotypes