Identification of novel variants in ten patients with Hermansky-Pudlak syndrome by high-throughput sequencing
| Autor: | Jesús María Hernández-Rivas, Margarida Lima, Mutlu Karkucak, José Padilla, Maria Luisa Lozano, Maria Trapero-Marugan, José Ramón González-Porras, Rosário Santos, Catarina Lau, Juan Francisco Ruiz-Pividal, Eduarda Couto, Verónica Palma-Barqueros, Rocío Benito, Kamila Janusz, Vicente Vicente, Nuria Bermejo, Jorge Oliveira, Marta Martín-Izquierdo, José Rivera, José María Bastida, Ana Marín-Quílez, Natalia Bohdan, Yusuf Yucel, Mónica Pereira, Sara Morais |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent 030204 cardiovascular system & hematology DNA sequencing 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases medicine Humans 030212 general & internal medicine Child skin and connective tissue diseases Blood Platelet Disorders integumentary system business.industry Genetic Variation High-Throughput Nucleotide Sequencing General Medicine Middle Aged medicine.disease Oculocutaneous albinism Dermatology eye diseases Pedigree Bleeding diathesis Inherited platelet disorder Phenotype Hermanski-Pudlak Syndrome Female Original Article Identification (biology) Hermansky–Pudlak syndrome business |
| Zdroj: | Ann Med |
| Popis: | 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 (n = 2) in HPS4, or the novel p.Arg822* homozygous variant (n = 1) in HPS3. In the case of two Turkish sisters, a novel missense homozygous HPS4 variant (p.Leu91Pro) was found. In two Portuguese families, genetic studies confirmed a previously reported nonsense variant (p.Gln103*) in DTNBP1 in three patients and a novel duplication (p.Leu22Argfs*33) in HPS6 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. |
| Databáze: | OpenAIRE |
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