Identification of putative genetic modifying factors that influence the development of Papillon–Lefévre or Haim–Munk syndrome phenotypes

Abstract

Summary Background Papillon–Lefévre syndrome (PLS; OMIM 245000) and Haim–Munk syndrome (HMS; OMIM 245010), which are both characterized by palmoplantar hyperkeratosis and periodontitis, are phenotypic variants of the same disease caused by mutations of the cathepsin C (CTSC) gene. Aim To identify putative genetic modifying factors responsible for the differential development of the PLS or HMS phenotypes, we investigated two Hungarian patients with different phenotypic variants (PLS and HMS) but carrying the same homozygous nonsense CTSC mutation (c.748C/T; p.Arg250X). Methods To gain insights into phenotype‐modifying associations, whole exome sequencing (WES) was performed for both patients, and the results were compared to identify potentially relevant genetic modifying factors. Results WES revealed two putative phenotype‐modifying variants: (i) a missense mutation (rs34608771) of the SH2 domain containing 4A (SH2D4A) gene encoding an adaptor protein involved in intracellular signalling of cystatin F, a known inhibitor of the cathepsin protein, and (ii) a missense variant (rs55695858) of the odorant binding protein 2A (OBP2A) gene, influencing the function of the cathepsin protein through the glycosyltransferase 6 domain containing 1 (GLT6D1) protein. Conclusion Our study contributes to the accumulating evidence supporting the clinical importance of phenotype‐modifying genetic factors, which have high potential to aid the elucidation of genotype–phenotype correlations and disease prognosis.

A novel missense variant in cathepsin C gene leads to PLS in a Chinese patient: A case report and literature review

“…According to our current knowledge, only 5 CTSC variants (c.145C>T, c.587T>C, c.748C>T, c.857A>G, and c.1337A>C) were reported in HMS patients, and all of them were also reported in PLS patients. In order to further clarify the relationship between genotypes and different phenotypes, Pap ÉM et al researched two patients with different phenotypes (PLS and HMS) but harboring the same nonsense CTSC variant by using whole‐exome sequencing (WES), the results found two potentially relevant putative phenotype‐modifying variants in HMS patient: a missense variant (rs34608771) of the SH2D4A gene and a missense variant (rs55695858) of the OBP2A gene, and they affected the intracellular signal transduction of the cystatin F, a known inhibitor of CTSC, and the function of CTSC through GLT6D1, respectively (Pap et al, 2020 ). However, haplotype analysis of 24 polymorphic markers in CTSC gene showed that PLS and HMS patients with the same homozygous nonsense CTSC gene variant carried the same haplotype, this result indicated that putative genetic‐modifying factors in the CTSC gene were nonexistent or other lifestyle or environmental factors also played important roles in different disease phenotypes observed among patients (Sulak et al, 2016 ).…”

“…Papilon‐Lefevre syndrome (PLS; OMIM 245000), categorized into type IV ectodermal dysplasia of palmoplantar, is an uncommon autosomal recessive inheritance and first reported in 1924 by Papillon and Lefevre (Papillon & Lefevre, 1924 ). The prevalence of PLS in the general population is about one to four cases per million and parental consanguinity accounts for more than 50% PLS cases (Pap et al, 2020 ). The dominant clinical symptoms of PLS are symmetrical and erythematous palmoplantar hyperkeratosis, which often worsen in autumn and winter and result in difficulties in walking and physical activities.…”

The first case report of Haim Munk disease with neurological manifestations and literature review

“…Haim-Munk syndrome (HMS), first described by Haim and Munk in 1965, 6 is the phenotypic variant of PLS with the CTSC gene mutation. 7 Haim-Munk characteristic signs are onychogryphosis, arachnodactyly, acroosteolysis, flat foot and permanent flexion contractures. 8 Periodontitis in Papillon-Lefévre syndrome and Haim-Munk syndrome arises from a failure to eliminate periodontal pathogens because of cathepsin C deficiency.…”