Abstract Number: PB1232
Meeting: ISTH 2022 Congress
Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Platelet Function Disorders, Hereditary
Background: Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism (OCA) and bleeding diathesis (due to a defect regarding melanosomes and platelet δ-granule secretion). The disease-associated genes encode either for multi-protein complexes BLOC-1 – BLOC-3 (biogenesis of lysosome-related organelles complex) or for AP-3 (adaptor protein-3). Patients with HPS type 2 (HPS-2) or HPS-10 present additionally with an immunological defect. BLOC-2 deficiencies (genes: HPS3, HPS5, HPS6) seem to have milder phenotypes especially regarding albinism.
Aims: To characterize the platelet defect of three patients (Pt.1-3) who suffer from bleeding diathesis. Only patient 3 showed apparent OCA.
Methods: Platelet count, platelet aggregometry (LTA), and flow cytometry (FC). Mepacrine analysis and whole mount-transmission electronmicroscopy (WM-TEM) (Pt.1, Pt.3). Panel next-generation sequencing (NGS). Western blot analysis and analysis of lymphocyte cytotoxicity (Pt.3).
Results: Platelet aggregometry showed impaired platelet function. FC revealed a severely reduced CD63 expression (hinting to δ-granule defect). Mepacrine uptake was profoundly impaired in the investigated patients implying lack of δ-granules as confirmed by WM-TEM. NGS identified a homozygous deletion of exon 6 in DTNBP1 for Pt.3. Western blot analysis confirmed the absence of the encoded protein dysbindin leading to the diagnosis HPS-7 (BLOC-1). Interestingly, this patient reported additionally recurrent bacterial infections. Analysis of lymphocyte cytotoxicity showed a slightly reduced NK degranulation previously documented in a more severe form in patients with HPS-2 or HPS-10. Pt.1 is carrier of compound heterozygous variants in the HPS3 gene (c.65C>G and c.1193G>A). A homozygous variant in HPS5 (c.760G>T) was identified in Pt.2. The novel missense variants were classified as variants of uncertain significance according to ACMG guidelines. For Pt.1, a specialized ophthalmological examination showed ocular albinism.
Conclusion(s): NGS can facilitate the process of identifying the genetic defects regarding the different HPS subtypes (even with mild clinical phenotype). Analysis of lymphocyte cytotoxicity in a patient with BLOC-1 deficiency showed a slightly reduced NK degranulation.
To cite this abstract in AMA style:
Boeckelmann D, Wolter M, Neubauer K, Weiss L, Schulze H, Sobotta F, Lenz A, Glonnegger H, Käsmann-Kellner B, Mann J, Ehl S, Zieger B. Hermansky-Pudlak syndrome: Identification of novel variants in the genes HPS3, HPS5, and DTNBP1 (HPS-7) and analysis of lymphocyte cytotoxicity for the HPS-7 patient [abstract]. https://abstracts.isth.org/abstract/hermansky-pudlak-syndrome-identification-of-novel-variants-in-the-genes-hps3-hps5-and-dtnbp1-hps-7-and-analysis-of-lymphocyte-cytotoxicity-for-the-hps-7-patient/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/hermansky-pudlak-syndrome-identification-of-novel-variants-in-the-genes-hps3-hps5-and-dtnbp1-hps-7-and-analysis-of-lymphocyte-cytotoxicity-for-the-hps-7-patient/