Hermansky-Pudlak Syndrome Type 8 (HPS8) via the BLOC1S3 Gene

Hermansky-Pudlak syndrome (HPS) is characterized by tyrosinase-positive oculocutaneous albinism, significant reduction in visual acuity often complicated by nystagmus, and bleeding diathesis resulting in bruising and sporadic and prolonged bleeding (Hermansky and Pudlak. Blood 14:162-169, 1959). Hair color ranges from white to brown and, along with skin color, is typically a shade lighter than is seen in unaffected family members. HPS patients may develop granulomatous colitis, with onset usually in their teens, or pulmonary fibrosis, with onset typically in their thirties or forties (Gahl et al. N Engl J Med 338:1258-1264, 1998). Similar characteristics are found with the related Chediak-Higashi syndrome (CHS) (OMIM 214500). Both HPS and CHS are storage pool disorders. The cellular origin of disease is attributed to abnormal storage granules such as melanosomes, platelet-dense granules, and lysosomes. Granule cargo includes pigment proteins, signaling molecules, and enzymes. Defects in granule biogenesis, structure, or function affect myriad downstream events. Micrographs of platelets from HPS patients often reveal a striking lack of dense granules, whereas granulocytes of CHS patients contain giant, aberrant storage granules.

HPS is an autosomal recessive disorder associated with the HPS1, AP3B1/(HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1/(HPS7), and BLOC1S3/(HPS8) genes. HPS is unusually common in Puerto Rico and is caused by unique variants in HPS1 and HPS3 (Santiago et al. J Invest Dermatol 126:85-90, 2006; Anikster et al. Nat Genet 28:376-380, 2001). In non-Puerto Ricans, variants in BLOC1S3/(HPS8) (OMIM 609762) account for ~2% of documented HPS cases (Oh et al. Am J Hum Genet 62:593-598, 1998) with the remaining cases being distributed as follows: HPS1 ~50%, AP3B1/(HPS2) ~6%, HPS3 ~15%, HPS4 ~12%, HPS5 ~5%, HPS6 ~4%, and DTNBP1/(HPS7) ~1%. To date, the only documented variant in BLOC1S3 that causes HPS8 was reported in a large family with HPS; all were homozygous for c.448delC that results in a frameshift and premature protein termination (Morgan et al. Am J Hum Genet 78:160-166, 2006). This family displayed the primary features of HPS (i.e. hypopigmentation, impaired visual acuity, and platelet dysfunction), but a bleeding tendency was not apparent in some individuals, and no individuals were affected by granulomatous colitis or pulmonary fibrosis.

HPS8 accounts for ~2% of documented HPS cases.

This test provides full coverage of all coding exons of the BLOC1S3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).