In a South Wales cohort of twelve familial HS probands, sequencing analysis of all genes encoding the gamma-secretase complex, including PSEN2 (Presenilin 2), the homologue of PSEN1, as well as the two homologues APH1A (Aph-1 Homolog A), and APH1B (Aph-1 Homolog B) failed to reveal HS-associated mutations in these genes; most of the variants identified were intronic or synonymous substitutions without a functional impact on protein and correlation with the clinical phenotype. This evidence concerns the gene PSEN2 and histiocytic sarcoma.