Papillon-Lefevre Syndrome (PLS) via the CTSC Gene

Papillon-Lefevre syndrome (PLS, OMIM 245000) is characterized by palmoplantar hyperkeratosis (thickening of skin on palms and souls of feet) and severe early onset periodontitis resulting in the premature loss of primary and secondary teeth (Gorlin et al. J Pediatr 65:895-908, 1964; Haneke Hum Genet 51:1-35, 1979). Palmoplantar keratosis usually develops in PLS patients by 3 years of age and varies from mild scaly skin to overt hyperkeratosis. Clinically, it is the periodontitis that distinguishes PLS from other forms of palmoplantar keratosis. The periodontitis of PLS is generally very aggressive and unresponsive to therapies, though in some very rare cases periodontitis is mild or late onset (Fardal et al. J Clin Periodontol 25:181-184, 1998). Consequently, most PLS patients lose all of their teeth by 20 years of age. PLS is ascertained mainly by dentists because of the severe periodontitis. Teeth are affected in the order of eruption and accompanied by inflamed periodontal tissue, bleeding of gums, pocket formation, and loosening with no sign of root resorption. In addition, some PLS patients may be more susceptible to infections because of an aberrant immune response (Haneke Hum Genet 51:1-35, 1979).

PLS exhibits an autosomal recessive pattern of inheritance and is caused by variants in the CTSC gene (Hart et al. J Med Genet 36:881-887, 1999; Toomes et al. Nat Genet 23:421-424, 1999). The frequency of PLS is approximately 1-4 per million people (Gorlin et al. J Pediatr 65:895-908, 1964). CTSC encodes cathepsin C (CTSC), a lysosomal protease and endopeptidase. CTSC is expressed in tissues involved in the immune response, e.g. bone marrow-derived myeloid and lymphoid cells, and plays an essential role in protein degradation and pro-enzyme activation including activation of granule serine proteases involved in a variety of immune responses (McGuire J Biol Chem 268:2458-2467, 1993; Rao et al. J Biol Chem 272:10260-10265, 1997). Consequently, loss of functional CTSC may be linked to an attenuated host response against bacteria in dental plaque and susceptibility to periodontitis (see Toomes et al. Nat Genet 23:421-424, 1999, for discussion). Causative variants in the CTSC gene include numerous missense and nonsense variants and to a lesser extent splicing variants, insertions, and deletions. No predominant variants have been reported, and no obvious genotype-phenotype correlation exists.

No variants in genes other than CTSC have been reported to cause PLS.

This test provides full coverage of all coding exons of the CTSC gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).