Abstract: Introduction: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder. Patients with HPS characteristically present with oculocutaneous albinism, nystagmus and increased bleeding tendency. The symptoms are caused by malfunction of lysosome related organelles (i.e. melanosomes, platelets). Patients with HPS typically show impaired platelet delta granule secretion. We report three patients (two brothers and another unrelated patient) who presented with these typical symptoms. Methods and Results: Platelet aggregometry and flow cytometry analyses revealed pathological platelet function and decreased platelet delta granule secretion. Using NGS panel analysis comprising all 10 HPS genes a defect in the HPS1 gene was identified. The brothers share compound heterozygous a novel splice variant (c.987+1[G>A]) and an already reported mutation (c.1189[delC]). Although the third patient is not related with the brothers, he presented with the same one base pair deletion c.1189[delC] compound heterozygous with another already reported base pair deletion (c.355[delC]). Conclusions: Since HPS1 patients are at risk to develop pulmonary fibrosis at middle age, early genetic diagnosis of the HPS type is important for prognosis and treatment. In this study we identified a novel splice site variant (c.987+1[G>A]) in the HPS1 gene, diagnosed the patients as HPS1 type and therefore, enabled adequate follow-up and therapy

Abstract: Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15-mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission