BLOC1S3 and Hermansky-Pudlak syndrome

Multiple independent studies have demonstrated that mutations in BLOC1S3 cause a distinct form of Hermansky-Pudlak syndrome. In a large consanguineous pedigree (PMID:16385460), affected individuals exhibiting features of oculocutaneous albinism, platelet dysfunction, and various visual defects were found to harbor a homozygous frameshift mutation. Additional case series expanded these findings through the identification of another truncating allele in BLOC1S3 in an Iranian patient with abnormal bleeding (PMID:22709368). More recently, independent families have been reported with different homozygous variants in BLOC1S3, reinforcing the genetic etiology of this HPS subtype (PMID:32687635).

Clinical validity for the association of BLOC1S3 with Hermansky-Pudlak syndrome is rated as Strong. This is based on the observation of at least two distinct loss‑of‑function variants segregating with disease in unrelated families, coupled with concordant experimental evidence demonstrating disruption of the BLOC‑1 complex, a key contributor to lysosome‑related organelle biogenesis.

At the genetic level, the condition follows an autosomal recessive inheritance pattern. Segregation analysis in the reported families indicates multiple affected relatives with co‐segregating truncating variants. In one representative case, the mutation c.448del (p.Gln150ArgfsTer75) was identified, which results in a premature frameshift and subsequent loss of normal protein function.

Functional studies have provided moderate support for pathogenicity by demonstrating that loss of BLOC1S3 destabilizes the BLOC‑1 complex and leads to abnormal melanosome localization. These findings are in line with the clinical observations of oculocutaneous albinism and bleeding diathesis seen in patients with Hermansky‑Pudlak syndrome.

There is no appreciable conflicting evidence; rather, multiple lines of evidence from consanguineous family studies, case reports, and functional assessments mutually reinforce the role of BLOC1S3 in disease pathogenesis. While additional cases have been reported, the available data already exceed ClinGen’s scoring maximum for genetic associations in this context.

In summary, the strong genetic evidence coupled with supportive functional data provide clear clinical utility in using BLOC1S3 mutation analysis for the diagnosis of Hermansky-Pudlak syndrome. Key take‑home message: BLOC1S3 loss‑of‑function mutations represent a robust biomarker for a distinct HPS subtype, enabling accurate diagnosis and informing patient management.

References

• American Journal of Human Genetics • 2006 • A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8) PMID:16385460
• Pigment Cell & Melanoma Research • 2012 • A BLOC-1 mutation screen reveals a novel BLOC1S3 mutation in Hermansky-Pudlak Syndrome type 8 PMID:22709368
• Pigment Cell & Melanoma Research • 2021 • Novel variants in the BLOC1S3 gene in patients presenting a mild form of Hermansky-Pudlak syndrome PMID:32687635

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