BLOC1S5 – Hermansky-Pudlak Syndrome

The association between BLOC1S5 (HGNC:18561) and Hermansky-Pudlak syndrome (MONDO_0019312) is supported by robust genetic and functional data. Two independent studies have identified homozygous truncating variants in BLOC1S5 in patients presenting with a clinical picture of mild oculocutaneous albinism, moderate bleeding diathesis, and platelet aggregation defects, establishing a strong genetic link (PMID:32565547, PMID:34058075).

Genetic evidence arises from the identification of distinct homozygous variants in unrelated probands. In one study, two unrelated patients harbored the variant c.345del (p.Val116fs) (PMID:32565547). In another study, a homozygous c.181delC (p.Val61Ter) variant was identified in a single patient, with healthy parents manifesting carrier status (PMID:34058075). Collectively, these findings from three probands across different families confirm an autosomal recessive mode of inheritance.

Segregation analysis further supports the pathogenicity of these variants. In the family trio described in the 2021 study, although only one individual was affected, the segregation pattern (affected proband with heterozygous unaffected parents) is consistent with autosomal recessive inheritance. Additional affected relatives with segregating variants were not reported, which is typical for rare recessive conditions.

Functional and experimental studies provide complementary evidence. Zebrafish models subjected to bloc1s5 knockdown recapitulated core clinical features including retinal hypopigmentation and bleeding diathesis, while in vitro assays demonstrated a failure to assemble the obligate BLOC-1 complex. These assays validate the disruptive effect of the identified variants on protein function, consistent with a loss‐of‐function mechanism (PMID:34058075).

Integration of genetic and functional data yields a coherent narrative: distinct truncating variants in BLOC1S5 disrupt BLOC-1 complex assembly, leading to the clinical manifestations of Hermansky-Pudlak syndrome. Although the evidence is derived from a limited number of probands (three in total), the compelling segregation and functional concordance provide strong support for this gene-disease association.

Key take‑home sentence: The combined genetic and experimental evidence supports the clinical utility of testing BLOC1S5 in patients with a suspected diagnosis of Hermansky-Pudlak syndrome.

References

• Genetics in medicine : official journal of the American College of Medical Genetics • 2020 • BLOC1S5 pathogenic variants cause a new type of Hermansky-Pudlak syndrome PMID:32565547
• Pigment cell & melanoma research • 2021 • A novel BLOC1S5‑related HPS‑11 patient and zebrafish with bloc1s5 disruption PMID:34058075

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