Hermansky-Pudlak Syndrome: Identification of Novel Variants in the Genes HPS3, HPS5, and DTNBP1 (HPS-7)

Abstract

Hermansky-Pudlak syndrome (HPS), a rare heterogeneous autosomal recessive disorder, is characterized by oculocutaneous albinism (OCA) and a bleeding diathesis due to a defect regarding melanosomes and platelet delta (δ)-granule secretion. Interestingly, patients with HPS type 2 (HPS-2) or HPS type 10 (HPS-10) present additionally with an immunological defect. We investigated three patients (IP1, IP2, and IP3) who suffer from a bleeding diathesis. Platelet aggregometry showed impaired platelet function and flow cytometry revealed a severely reduced platelet CD63 expression hinting to either a defect of platelet delta granule secretion or a decreased number of delta granules in these patients. However, only IP3 presents with an apparent OCA. We performed panel sequencing and identified a homozygous deletion of exon 6 in DTNBP1 for IP3. Western analysis confirmed the absence of the encoded protein dysbindin confirming the diagnosis of HPS-7. 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. IP1 is carrier of two 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 IP2. The novel missense variants were classified as VUS (variant of uncertain significance) according to ACMG guidelines. For IP1 with the compound heterozygous variants in HPS3 a specialized ophthalmological examination showed ocular albinism. HPS3 and HPS5 encode subunits of the BLOC-2 complex and patients with HPS-3 or HPS-5 are known to present with variable/mild hypopigmentation.

Classic Light Transmission Platelet Aggregometry: Do We Still Need it?

“…Hence, careful interpretation and communication of these results is essential to avoid misinterpretation and misdiagnosis. 123 124 125…”

“…Hence, careful interpretation and communication of these results is essential to avoid misinterpretation and misdiagnosis. [123][124][125] Further research approaches are developed and implemented to assess platelet function and properties using proteomics, lipidomics, and transcriptomics, revealing that platelets no longer represent a homogeneous cell population as previously thought. Instead, they constitute a heterogeneous, interactive population with distinct subgroups that either protect against or contribute to disease processes.…”

A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger

“…To extract genomic DNA from EDTA blood, we used standard procedures and the DNeasy blood and tissue kit produced by Qiagen (Qiagen GmbH, Hilden, Germany), and we quantified the results using a Qubit 2.0 fluorometer (ThermoFisher Scientific, Scientific, Waltham, MA, USA). DNAs from the German index patients (A I.1, A I.2, and B I.1) were analyzed by high-throughput sequencing (HTS) of a 95-gene panel using a custom-designed Nextera Rapid Enrichment Kit (Illumina, Inc., San Diego, CA, USA) previously described [ 49 ], followed by sequencing on a MiSeq (Illumina). For bioinformatics analysis, Sequence Pilot (JSI medical systems) and Alamut Visual Plus (SOPHiA GENETICS, Rolle, Switzerland) were used.…”

Inherited Platelet Disorders: A Short Introduction

“…Panel sequencing helps identify even rare types of HPS (e.g., HPS-7 and HPS-11). 23,24 Patients with the Chediak-Higashi syndrome (CHS) (OMIM #214500) suffer from an immunodeficiency as the most important clinical feature. In addition, they present with oculocutaneous albinism, neurological abnormalities, and a mild tendency to bleed due to alterations in the LYST (lysosomal trafficking regulator/CHS1) gene.…”