Background: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by oculocutaneous albinism and platelet dysfunction. We report on a novel HPS6 homozygous frameshift variant (c.1919_1920delTC; p.Val640Glyfs*29) in a nonconsanguineous Caucasian family with two affected siblings (index patients) who presented with oculocutaneous albinism at birth and a mild bleeding phenotype during childhood and adolescence.
Procedure: Genetic analysis was conducted by panel-based next-generation sequencing (NGS) and Sanger sequencing. Platelets of the index patients, their parents, and the unaffected sister were then comprehensively evaluated by luminoaggregometry, whole blood flow cytometry, immunoblotting, immunofluorescence, and transmission electron microscopy.
Results: The homozygous frameshift variant in HPS6 gene detected by panel-based NGS and its segregation in the family was confirmed by Sanger sequencing. Flow cytometric analysis of the patients' platelets revealed a substantially decreased mepacrine uptake and release upon activation with a thrombin receptor agonist. Electron microscopy of resting platelets confirmed diminished dense granule content and enhanced vacuolization. Reduced release of adenosine triphosphate and CD63 neoexposition upon activation indicated not only a lack of dense granule content, but even an impairment of dense granule release.
Conclusions: 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.
Keywords: Hermansky-Pudlak syndrome; bleeding; mutation; oculocutaneous albinism; platelet disorder.
© 2016 Wiley Periodicals, Inc.