Synonymous but Significant: New Findings of Pathological Variants in Hermansky-Pudlak Syndrome

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and systemic complications, including bleeding tendencies. While 11 genes associated with HPS have been identified, cases of HPS5 remain exceedingly rare, particularly in Japan. Here, we report two Japanese patients with novel pathological HPS5 variants, expanding the genetic spectrum of this disorder. Both patients exhibited typical features of mild skin and hair hypopigmentation, and significant ocular involvement. Genetic analysis revealed a heterozygous nonsense variant, NG_008877.1 (NM_181507.2): c.2275G>T, in both patients, inherited from their fathers. Additionally, maternal variants NG_008877.1 (NM_181507.2): c.2952-13G>A and NG_008877.1 (NM_181507.2): c.1128A>G were identified in patient 1 and patient 2, respectively. These variants, initially presumed non-pathogenic, were found to induce alternative splicing, leading to truncated protein production. Our findings highlight the functional importance of synonymous variants and their potential role in HPS. This report represents the first documented case of a synonymous pathogenic variant associated with HPS and underscores the need for comprehensive genetic and transcriptomic analyses in rare genetic disorders.