Hermansky-Pudlak Syndrome (HPS) Panel

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. PubMed ID: 13618373). Hair and skin color are typically shades lighter than seen in unaffected relatives and HPS patients are at a high risk for skin damage or skin cancers from sun exposure. HPS patients may experience bleeding problems such as frequent epistaxis, easy bruising, and prolonged bleeding after injury or surgery.  HPS patients typically have symptoms from birth, but some patients may also develop immunodeficiencies, and later-onset conditions including granulomatous colitis (usually in teens), or pulmonary fibrosis (typically in thirties or forties) (Huizing et al. 2008. PubMed ID: 18544035; Gahl et al. 1998. PubMed ID: 9562579). The frequency of HPS is between 1 in 500,000 to 1 in 1,000,000 in most of the world, however, HPS is unusually common in regions of Puerto Rico where approximately 1:1800 individuals are affected and the estimated carrier frequency is 1 in 21 (Wildenberg et al. 1995. PubMed ID: 7573033). 

Similar clinical characteristics are also found in patients with the related disorder Chediak-Higashi Syndrome (CHS). Both HPS and CHS are attributed to abnormalities in lysosome-related organelles including melanosomes in melanocytes, dense granules in platelets, lytic granules in T cells, basophilic granules, and azurophilic granules in neutrophils. HPS is marked by a near absence of platelet dense granules (Witkop et al. 1987. PubMed ID: 3120578) whereas CHS is distinguished by giant granules in neutrophils, eosinophils, and other granulocytes (Introne et al. 1999. PubMed ID: 10527680).

Simultaneous genetic testing for a large subset of Hermansky-Pudlak-related genes may provide the most efficient approach for establishing an accurate and timely diagnosis and for distinguishing HPS from similar disorders like CHS and other skin / hair / and eye pigmentation disorders. Identifying a particular HPS subtype is also valuable for determining whether a patient is at a higher risk for additional HPS complications such as immunodeficiency and pulmonary fibrosis.

HPS is a genetically heterogeneous, autosomal recessive disorder associated with the HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1 (HPS7), BLOC1S3 (HPS8), BLOC1S5, BLOC1S6 (HPS9), and AP3D1 (HPS10) genes (De Jesus Rojas et al. 2020. PubMed ID: 32279294; Pennamen et al. 2020. PubMed ID: 32565547). HPS proteins belong to the BLOC (Biogenesis of Lysosome-related Organelle Complexes) proteins that are required for proper formation, function, and trafficking of lysosome-related vesicles (Huizing et al. 2008. PubMed ID: 18544035).

Most affected Puerto Ricans harbor either a 16 bp duplication in HPS1 or a 3.9kb deletion in HPS3 (Anikster et al. 2001. PubMed ID: 11455388; Santiago et al. 2006. PubMed ID: 16417222). In non-Puerto Ricans, pathogenic HPS1 variants account for ~50% of cases (Oh et al. 1998. PubMed ID: 9497254) 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%, and isolated cases for BLOC1S6 (HPS9) and AP3D1 (HPS10) (Ammann et al. 2016. PubMed ID: 26744459; Mohammed et al. 2019. PubMed ID: 30472485).

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 severe forms of HPS with more pronounced albinism, development of colitis, a high occurrence of pulmonary fibrosis, and accelerated ceroid lipfusin accumulation in lung, liver, bone marrow, kidney, and other cells (Huizing and Gahl 2002. PubMed ID: 12125811; Hussain et al. 2006. PubMed ID: 16431308; Huizing et al. 2008. PubMed ID: 18544035). Patients with HPS2 are also more likely to develop pulmonary fibrosis, but in general this is not a characteristic associated with the remaining HPS subtypes (Huizing et al. 2004. PubMed ID: 15296495; Gochuico et al. 2012. PubMed ID: 22009278). Patients with HPS2, HPS9, and HPS10 are also known to have an increased risk for infections due to accompanying immunodeficiencies (Huizing et al. 2002. PubMed ID: 11809908; Badolato et al. 2012. PubMed ID: 22461475; Ammann et al. 2016. PubMed ID: 26744459). One patient with HPS10 had neurological abnormalities that were similar to those observed in Ap3d1 null mice (Kantheti et al. 1998. PubMed ID: 9697856).

Pathogenic variants for the HPS genes include missense, splicing, and various loss-of-function variants; the variant types for HPS1 in one study are distributed as follows: 1% start‐loss, 26% frameshift, 20% missense, 14.5% nonsense, 24% insertions and/or deletions, and 14.5% splice site variants (Huizing et al. 2020. PubMed ID: 31898847). Variant types are distributed roughly similarly among the other HPS genes with the most notable difference being HPS4 in which 47% of the variants are nonsense variants (Huizing et al. 2020. PubMed ID: 31898847).  With the exception of the 3.9kb deletion in the HPS3 gene that is common among Puerto Ricans, large deletions and duplications are not common among the HPS genes. De novo variants are also rare for the HPS genes (Huizing et al. 2020. PubMed ID: 31898847). Mouse models suggest loss of HPS proteins is tolerated for viability (see for example Feng et al. 1997. PubMed ID: 9158155; Kantheti et al. 1998. PubMed ID: 9697856). 

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

The clinical sensitivity of testing for HPS is unknown, however testing large cohorts with clinical features of HPS has identified previously undiagnosed patients. For example, in a cohort of 990 patients with albinism, a screen of 19 known albinism genes revealed a genetic diagnosis in ~72% of patients; HPS was confirmed in 49 of the patients (Lasseaux et al. 2018. PubMed ID: 29345414). In another cohort of Arab patients with albinism, likely pathogenic variants in HPS genes were identified in 8 of 21 patients (Khan et al. 2016. PubMed ID: 26785811). Another study of 159 patients with bleeding and platelet disorders not necessarily associated with albinism, identified 6 patients with HPS suggesting that HPS may be underdiagnosed in patients with mild phenotypes (Simeoni et al. 2016. PubMed ID: 27084890).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides ~100% coverage of all coding exons of the genes 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 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).