Next-generation sequencing identified different types of Hermansky-Pudlak syndrome associated with phenotype variability

Objective Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of 10 rare autosomal recessive multisystem disorders. HPS-associated genes encode components of four proteins complexes: BLOC-1, 2, 3 (biogenesis of lysosome‐related organelles complex 1-3) and the transporter complex AP-3 (adaptor protein-3). The main symptoms are bleeding tendency and oculocutaneous albinism. In HPS1 and HPS2 pulmonary fibrosis and granulomatous colitis can occur, in HPS2 and HPS10 immune deficiency is associated. Milder phenotypes have been described for HPS3, HPS5 and HPS6. The symptoms are caused by malfunction of lysosome related organelles: platelet δ-granules, melanosomes, lamellar bodies in lung cells and lytic and azurophil granules in neutrophiles. Identification of the HPS subtype is important for prognosis, clinical management and treatment options. We investigated 5 patients and 8 family members to identify the underlying disease.

Material and Methods Aggregometry and flow cytometry for platelet function studies. Targeting enrichment of a large gene panel followed by sequencing on a MiSeq. SeqPilot (JSI), Alamut® Visual, in silico pathogenicity prediction for data analysis. Sanger sequencing for segregation analysis.

Results Aggregometry revealed impaired platelet function after ADP stimulation. Flow cytometry showed severely reduced δ-granule secretion. Using NGS we diagnosed three young boys with HPS1 who have an increased risk to develop pulmonary fibrosis later on. So far, only very few HPS7 patients have been reported. We identified a 59 year old female with a lifelong history of bleeding symptoms to suffer from HPS7. In a girl who did not show any sign of cutaneous albinism, however, displayed ocular albinism likely pathogenic variants in the HPS3-gene were identified. The HPS1 and HPS3 patients had compound heterozygous pathogenic/likely pathogenic variants (3 novel). The HPS7 patient showed a novel homozygous exon 6 deletion in DTNBP1 (gene associated with HPS7).

Conclusion Depending on the type and location of the mutation in the HPS genes the phenotype can vary significantly. Therefore, it is possible that patients with no apparent sign of albinism may be overseen and underdiagnosed. Furthermore, patients with oculocutaneuos albinism should be investigated for platelet function defect to prevent severe and life-threatening bleedings in case of surgery, especially in mucocutaneous areas.

Publication History

Article published online:
18 June 2021