HPS6 – Hermansky-Pudlak Syndrome Type 6

HPS6 (HPS6) encodes a subunit of the biogenesis of lysosome‐related organelles complex‐2 (BLOC‐2). Biallelic pathogenic variants in HPS6 cause Hermansky-Pudlak syndrome 6, an autosomal recessive disorder characterized by oculocutaneous albinism and a platelet storage‐pool defect.

In three independent cohorts, whole‐exome and targeted sequencing identified biallelic HPS6 variants in 6 probands (3 families) ([PMID:26823395]; [PMID:35054407]; [PMID:38091959]). Segregation analysis confirmed autosomal recessive inheritance in affected siblings and consanguineous relatives, with no phenotype in heterozygous carriers.

The variant spectrum includes missense and truncating alleles across the single‐exon HPS6 gene. A representative loss‐of‐function change is c.1789del (p.Ala597GlnfsTer16) ([PMID:35054407]). Other reported alleles include c.1136C>A (p.Ser379Ter) and compound heterozygous truncations such as c.1674dup and c.503_504del in different families ([PMID:38091959]).

Functional studies in patient‐derived melanocytes demonstrate defective trafficking of tyrosinase and TYRP1 to melanosomes, consistent with BLOC‐2 complex malfunction and explaining the hypopigmentation phenotype ([PMID:19843503]). Platelet assays confirm a dense‐granule deficiency underlying bleeding diathesis.

No conflicting data have been reported; HPS6 patients uniformly present with nystagmus, foveal hypoplasia, hypopigmentation (HP:0007375), and bleeding diathesis (HP:0001873) but lack severe pulmonary fibrosis or granulomatous colitis seen in other HPS subtypes.

Collectively, these genetic and cellular data meet ClinGen criteria for a Strong gene–disease association. HPS6 should be included in genetic testing panels for unexplained oculocutaneous albinism with bleeding symptoms; early molecular diagnosis enables anticipatory management of hemorrhagic risk.

References

• The British journal of ophthalmology • 2016 • The ophthalmic presentation of Hermansky-Pudlak syndrome 6. PMID:26823395
• Life (Basel, Switzerland) • 2021 • Two Novel Homozygous HPS6 Mutations (Double Mutant) Identified by Whole-Exome Sequencing in a Saudi Consanguineous Family Suspected for Oculocutaneous Albinism. PMID:35054407
• Journal of medical genetics • 2009 • Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6. PMID:19843503
• Ophthalmic research • 2024 • Novel Variants of HPS6 Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of HPS6 Variants. PMID:38091959

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