PB1242 - The phenotypic and genetic heterogeneity of Hermansky-Pudlack Syndrome

Tuesday, July 12, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Co-Author(s)

FS

Filipa Santos

Assistent Physician, MD
Thrombosis and Hemostasis Unit, Clinical Haematology Service, Centro Hospitalar Universitário do Porto, Porto, Portugal
Porto, Porto, Portugal
MC

Maria Coutinho

MD, Assistent in Hematology
Thrombosis and Haemostasis Unit, Centro Hospitalar Universitário do Porto, Porto, Portugal
Porto, Porto, Portugal

Presenting Author(s)

Catarina Monteiro, MsC

MSc, Clinical Biochemistry
Unidade de Trombose e Hemostase, Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal; Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, CHUPorto; Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas (UMIB/ICBAS/UP) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal

Co-Author(s)

MP

Mónica Pereira

MSc, Biochemistry
Unidade de Trombose e Hemostase, Serviço de Hematologia Clínica, Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal; Unidade de Investigação Biomédica (UMIB/ICBAS/UP) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal
RM

Rui Matos

Lab Technician
Thrombosis and Hemostasis Unit, Clinical Haematology Service, Centro Hospitalar Universitário do Porto, Porto, Portugal
Porto, Porto, Portugal
AG

Ana Gonçalves

MSc, Molecular and Cell Biology
Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal; Unidade de Investigação Biomédica (UMIB/ICBAS/UP) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal
EC

Eugénia Cruz, MD, PhD

Consultant Physician, MD, PhD
Thrombosis and Hemostasis Unit, Clinical Haematology Service, Centro Hospitalar Universitário do Porto, Porto, Portugal
Porto, Porto, Portugal
RS

Rosário Santos

PhD, Pharmaceutical Sciences
Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário do Porto, Porto, Portugal
Porto, Porto, Portugal
SM

Sara Morais

Senior Physician, MD
Thrombosis and Hemostasis Unit, Clinical Haematology Service, Centro Hospitalar Universitário do Porto, Porto, Portugal
Porto, Porto, Portugal

Background: Hermansky-Pudlak syndrome (HPS) is a group of 11 autosomal recessive multisystemic disorders. All individuals exhibit oculocutaneous albinism (OCA) and a bleeding diathesis; additional features, like pulmonary fibrosis, granulomatous colitis, and immunodeficiency, can occur in some subtypes. Identification of the HPS subtype is important for prognosis and clinical management, making early molecular diagnosis important.

Aims: To assess the clinical and platelet phenotype and genetic defects in nine patients with suspected HPS, from 6 unrelated families from a Portuguese unique centre.

Methods: Nine patients from one consanguineous and five non-consanguineous families, from the north of Portugal, were included. Bleeding was evaluated by ISTH-BAT score (BS), patient platelets were evaluated by functional studies (lumiaggregometry and flow cytometry) and by electron microscopy (EM). Patients DNA were analyzed by high-throughput sequencing (HTS) using a 92-gene panel related to Hemostasis. Sequence variants classification was performed according to ACMG recommendations.

Results: All patients [3M/6F, median age 7 years (min-max 1-56)] had confirmed OCA and platelet disfunction (impaired platelet aggregation and ATP release, and absent/reduced dense granules by EM). The median BS was 8 (min-max 6-11). Molecular diagnosis revealed in two non-related and non-consanguineous families, a nonsense variant in exon 5 of DTNBP1, and in another family, a five base pair duplication in the single exon of HPS6: these three families were previously reported (Bastida JM, Morais S et al. 2019). In the fourth family, a nonsense homozygous variant in HPS6 and in the fifth family, a nonsense variant in exon 13 and a frameshift variant in exon 2 of HPS3 in compound heterozygous, were identified. Interestingly, in a sixth family, four heterozygous missense variants in HPS1, HPS3, LYST, and SLC45A2 were identified.

Conclusion(s): The HTS technology simplified the molecular diagnosis of HPS, and at same time, underline the heterogeneously and complexity of the phenotype/genotype correlations.