PB1307 - Molecular profiling of a patient with combined thrombocytopenia and connective tissue disorder

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

PB

Perla Bandini

PhD student
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain

Co-Author(s)

FL

Francisco Javier Lucas

Hematologist
Departamento de Hemostasia y Trombosis, Hospital General Universitario Dr. Balmis, Alicante, Spain.
Alicante, Comunidad Valenciana, Spain

Presenting Author(s)

NB

Nina Borràs

PhD
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain

Co-Author(s)

LM

Laura Martin-Fernandez

PhD
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain.
Barcelona, Catalonia, Spain
AM

Ana Marco-Rico

Hematologist
Departamento de Hemostasia y Trombosis, Hospital General Universitario Dr. Balmis, Alicante, Spain
Alicante, Comunidad Valenciana, Spain
NC

Natàlia Comes

Technician
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain
LR

Lorena Ramírez

Technician
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain
CH

Carlos Hobeich

Bioinformatician
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain
FV

Francisco Vidal

Head of Unit, PhD
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain
IC

Irene Corrales

Main researcher, PhD
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain

Background: Heritable disorders of connective tissue (HDCT) are rare diseases caused by defects in the elements of extracellular matrix and manifest predominantly with joint hypermobility and skin laxity, but also with bleeding. However, genetic diagnosis of patients with hemorrhagic diathesis is usually focused, when available, on sequencing of the coagulation cascade and platelet-related genes.

Aims: We present the case of a patient having sings of both inherited platelet disorder (IPD) and HDCT. The aim was to identify the molecular defect associated with the patients’ phenotype using a whole exome sequencing (WES) strategy.

Methods: WES was performed in NextSeq500 system. Variants were identified, annotated and filtered using a list of 318 genes related with bleeding. Candidate variants were confirmed by Sanger sequencing.

Results: The patient was a 28 years old woman presenting with thrombocytopenia (122x10e9 platelets/L), joint hypermobility, delayed scarring, gingivorrhagia, hematomas and menorrhagia (ISTH-BAT=3). WES analysis revealed two novel variants: NM_001754.4:c.614-2_614-1ins614-5_614-2inv in RUNX1, a gene linked to thrombocytopenia associated with myeloid malignancy, and NM_000088.3:c.2558T>C, p.Ile853Thr in COL1A1, a gene associated with Ehlers-Danlos Syndrome (EDS), which is a type of HDCT. The impact of the variants was assessed with different in silico prediction tools (Table 1).

Conclusion(s): We here describe the case of a patient with bleeding due to a combined IPD and HDCT presenting two new variants associated with the phenotype. This highlights the relevance of assessing signs of HDCT during the clinical examination of patients with bleeding, as they can be related with the hemorrhagic symptoms. Segregation studies will help to demonstrate the correlation with the phenotype, and RNA sequencing will be performed to determine the effect of the splicing variant in RUNX1. Molecular diagnosis will facilitate the monitoring of bleeds, risk of malignancy and musculoskeletal complications linked to EDS.

Funding: ISCIII (PI18/01492, PI23/01672, CIBERCV), RFVE and Fundació Privada Catalana de l’Hemofília.