Identification of novel variants in ten patients with Hermansky-Pudlak syndrome by high-throughput sequencing
Creators: name: Bastida, Jose María
name: Morais, Sara
name: Palma-Barqueros, Veronica
name: Benito, Rocio
name: Bermejo, Nuria
name: Karkucak, Mutlu
name: Trapero-Marugan, Maria
name: Bohdan, Natalia
name: Pereira, Mónica
name: Marin-Quilez, Ana
name: Oliveira, Jorge
name: Yucel, Yusuf
name: Santos, Rosario
name: Padilla, Jose
name: Janusz, Kamila
name: Lau, Catarina
name: Martin-Izquierdo, Marta
name: Couto, Eduarda
name: Ruiz-Pividal, Juan Francisco
name: Vicente, Vicente
name: Hernández-Rivas, Jesus Maria
name: González-Porras, Jose Ramon
name: Lozano, Maria Luisa
name: Lima, Margarida
name: Rivera, Jose
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: 69999 Biological Sciences not elsewhere classified
subject: Cancer
subject: Hematology
subject: Computational Biology

description: Hermansky-Pudlak syndrome (HPS) is a rare inherited platelet disorder characterized by bleeding diathesis, oculocutaneous albinism (OCA) and a myriad of often-serious clinical complications. We established the clinical and laboratory phenotype and genotype of six unrelated pedigrees comprising ten patients with clinical suspicion of HPS; including platelet aggregation, flow cytometry, platelet dense granule content, electron microscopy and high-throughput sequencing (HTS). The clinical presentation showed significant heterogeneity and no clear phenotype-genotype correlations. HTS revealed two known and three novel disease-causing variants. The Spanish patients carried a homozygous p.Pro685Leufs17* deletion (<i>n</i> = 2) in <i>HPS4</i>, or the novel p.Arg822* homozygous variant (<i>n</i> = 1) in <i>HPS3</i>. In the case of two Turkish sisters, a novel missense homozygous <i>HPS4</i> variant (p.Leu91Pro) was found. In two Portuguese families, genetic studies confirmed a previously reported nonsense variant (p.Gln103*) in <i>DTNBP1</i> in three patients and a novel duplication (p.Leu22Argfs*33) in <i>HPS6</i> in two unrelated patients. Our findings expand the mutational spectrum of HPS, which may help in investigating phenotype-genotype relationships and assist genetic counselling for affected individuals. This approach is a proof of principle that HTS can be considered and used in the first-line diagnosis of patients with biological and clinical manifestations suggestive of HPS.Key messagesWe established the relationships between the clinical and laboratory phenotype and genotype of six unrelated pedigrees comprising ten patients with clinical suspicion of HPS.Molecular analysis is useful in confirming the diagnosis and may offer some prognostic information that will aid in optimizing monitoring and surveillance for early detection of end-organ damage.This approach is a proof of principle that HTS can be considered and used in the first-line diagnosis of patients with biological and clinical manifestations suggestive of HPS. We established the relationships between the clinical and laboratory phenotype and genotype of six unrelated pedigrees comprising ten patients with clinical suspicion of HPS. Molecular analysis is useful in confirming the diagnosis and may offer some prognostic information that will aid in optimizing monitoring and surveillance for early detection of end-organ damage. This approach is a proof of principle that HTS can be considered and used in the first-line diagnosis of patients with biological and clinical manifestations suggestive of HPS.