A novel two‐nucleotide deletion in HPS6 affects mepacrine uptake and platelet dense granule secretion in a family with Hermansky–Pudlak syndrome

Abstract

Our results demonstrate that the novel loss-of-function variant in the HPS6 subunit of biogenesis of lysosome-related organelles complex 2 is pathologic and leads to a reduced platelet dense granules and their release. The findings are compatible with an impaired platelet function and hence an enhanced bleeding risk. In future, a valid genotype-phenotype correlation may translate into best supportive care, especially regarding elective surgery or trauma management.

Weak correlation of bleeding scores to platelet electron microscopy: A retrospective chart review of pediatric patients with delta‐storage pool disorder

“…Given that the cumulative body of evidence has shown the poor correlation of PEM against platelet aggregation studies and the results of our current study, which additionally has shown the poor correlation of PEM to lumiaggregometry and bleeding symptoms, it is difficult to recommend PEM as a useful diagnostic test for patients with a bleeding disorder . Whether qualitative or secretion abnormalities of the dense granules exist in these patients, which may be transient or too mild in nature to be detected by standard platelet aggregometry testing, remains to be determined . However, it is clear from our data that dense granule quantity does not alone impact proper hemostasis.…”

“…1,10,12,13,15,17,18 Whether qualitative or secretion abnormalities of the dense granules exist in these patients, which may be transient or too mild in nature to be detected by standard platelet aggregometry testing, remains to be determined. 9,35 However, it is clear from our data that dense granule quantity does not alone impact proper hemostasis. Rather, clinical consideration may need to be given to connective tissue disorders or hypermobility syndromes, as they are well known to cause bleeding symptoms and may easily be underrecognized.…”

Use of Targeted High-Throughput Sequencing for Genetic Classification of Patients with Bleeding Diathesis and Suspected Platelet Disorder

“…Additional functional assays and segregation analysis provided evidence that the novel homozygous frameshift variant in the HPS6 gene of a 17-year-old adolescent (case 1) is causative for the clinical phenotype of HPS and was thus considered as class 4. 34 Comprehensive genetic investigation was necessary to clear up the pathogenesis of a gray platelet-like syndrome in a family with life-threatening bleeding diathesis (case 24), ending up in the first description of an autosomal recessive GFI1B nonsense mutation in the alternatively spliced exon 9, which selectively leads to severe macrothrombocytopenia and platelet dysfunction without critically impairing erythropoiesis. 7 Two other adult patients with familial thrombocytopenia (cases 14 and 27) showed variants in the genes MYH9 and ACTN1 that are associated with thrombocytopenia due to impaired megakaryocytic and platelet cytoskeleton regulation according to previously described single reports.…”

Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome

“…The SNPs are typically identified by Sanger sequencing. Alternatively, next generation sequencing approaches are sensitive enough to detect both the SNP and the microdeletion by a reduced number of reads, when the relevant probes have been carefully selected to cover the non‐coding 5′UTR and intronic SNPs (Nicchia et al , ; Andres et al , ). The clinical features are overall specific and rather distinct, but a small series of differential diagnoses and additional non‐haematological features might mask the diagnosis.…”