Hermansky-Pudlak Syndrome Type 9 (HPS9) via the BLOC1S6/PLDN Gene

Hermansky-Pudlak Syndrome (HPS) is characterized by tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and significant reduction in visual acuity often characterized by nystagmus, reduced retinal and iris pigmentation, and foveal hypoplasia (Hermansky and Pudlak 1959). Hair and skin color are typically shades lighter than is seen in unaffected relatives. HPS patients may experience frequent epistaxis, easy bruising, and prolonged bleeding with injury or surgery. HPS patients may also develop immunodeficiencies, granulomatous colitis, with onset usually in their teens, and/or pulmonary fibrosis, with onset typically in their thirties or forties (Huizing et al. 2008; Gahl et al. 1998). Similar characteristics are found with the related Chediak-Higashi Syndrome (CHS). HPS and CHS are disorders of storage granules, e.g. melanosomes, platelet-dense granules, lysosomes, and lytic granules. A hallmark of HPS is a lack of platelet dense granules, as seen on electron micrographs (Witkop et al. 1987). CHS is distinguished by giant azurophilic granules in neutrophils, eosinophils, and other granulocytes (Introne et al. 1999).

HPS is a genetically heterogeneous autosomal recessive disorder associated with the HPS1, AP3B1/(HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1/(HPS7), BLOC1S3/(HPS8), and BLOC1S6(HPS9) genes. HPS proteins belong to the BLOC (Biogenesis of Lysosome-related Organelle Complexes) groups of proteins that function during formation and/or trafficking of lysosme-related vesicles (Huizing et al. 2008). HPS is unusually common in Puerto Rico where regions of the country have an estimated carrier frequency as high as 1 in 21 (Wildenberg et al. 1995). Most affected Puerto Ricans harbor either a 16bp duplication in HPS1 or a 3.9kb deletion in HPS3 (Anikster et al. 2001; Santiago et al. 2006). In non-Puerto Ricans, HPS1 mutations account for ~50% of cases (Oh et al. 1998) with the remaining cases being distributed as follows: AP3B1/(HPS2) ~1%, HPS3 ~13%, HPS4 ~12%, HPS5 ~9%, HPS6 ~7%, DTNBP1/(HPS7) ~1%, BLOC1S3/(HPS8) ~1%, BLOC1S6(HPS9) only two patients to date, homozygous for the c.232 C>T (Gln78Term) pathogenic variant in the BLOC1S6 / HPS9 / PLDN gene, have been reported to date (Cullinane et al. 2011; Badolato et al. 2012).

The severity of HPS varies among the subtypes and among family members having the same subtype, but some general genotype / phenotype correlations have emerged. Patients with HPS1 or HPS4 generally have more severe forms of HPS with more pronounced albinism, development of colitis (Hussain et al. 2006), a high occurrence of pulmonary fibrosis (Huizing et al. 2008), and accelerated ceroid lipfusin accumulation in lung, liver, bone marrow, kidney, and other cells (Huizing and Gahl 2002). The remaining subtypes are generally not associated with pulmonary fibrosis (Huizing et al. 2004), however, HPS2 and HPS9 have been associated with immunodeficiencies (Huizing et al. 2002; Badolato et al. 2012).

Pathogenic variants in the BLOC1S6 / PLDN gene have been reported in only two patients to date (Cullinane et al. 2011; Badolato et al. 612012).

This test provides full coverage of all coding exons of the BLOC1S6 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).