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Thromb Haemost 2024; 124(07): 628-640
DOI: 10.1055/s-0043-1778070
Cellular Haemostasis and Platelets

Gaining Insights into Inherited Bleeding Disorders of Complex Etiology in Pediatric Patients: Whole-Exome Sequencing as First-Line Investigation Tool

Perla Bandini 
1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
2   Medicina Transfusional, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
3   Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Barcelona, Spain
,
Nina Borràs
1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
2   Medicina Transfusional, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Ruben Berrueco
4   Servei d'Hematologia Pediàtrica, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu de Barcelona (IRP-HSJD), Universitat de Barcelona, Barcelona, Spain
5   Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain
,
Susanna Gassiot
6   Servei de Diagnòstic de Laboratori, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu de Barcelona (IRP-HSJD), Universitat de Barcelona, Barcelona, Spain
,
Laura Martin-Fernandez 
1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
2   Medicina Transfusional, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Edurne Sarrate
6   Servei de Diagnòstic de Laboratori, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu de Barcelona (IRP-HSJD), Universitat de Barcelona, Barcelona, Spain
,
Natàlia Comes
1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
2   Medicina Transfusional, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Lorena Ramírez
1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
2   Medicina Transfusional, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Carlos Hobeich
1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
2   Medicina Transfusional, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Francisco Vidal 
1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
2   Medicina Transfusional, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
7   Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III (ISCIII), Madrid, Spain
,
Irene Corrales
1   Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
2   Medicina Transfusional, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
7   Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III (ISCIII), Madrid, Spain
› Author Affiliations Funding This study was supported by the Spanish Ministry of the Economy and Competitiveness (MINECO, Ministerio de Economía y Competitividad), Instituto de Salud Carlos III (ISCIII) (PI18/01492), Real Fundación Victoria Eugenia, and Fundació Privada Catalana de l'Hemofília. CIBERCV is an initiative of ISCIII, co-financed by the European Regional Development Fund (ERDF), “A way to build Europe.”
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Abstract

Introduction Investigation of the molecular basis of inherited bleeding disorders (IBD) is mostly performed with gene panel sequencing. However, the continuous discovery of new related genes underlies the limitation of this approach. This study aimed to identify genetic variants responsible for IBD in pediatric patients using whole-exome sequencing (WES), and to provide a detailed description and reclassification of candidate variants.

Material and Methods WES was performed for 18 pediatric patients, and variants were filtered using a first-line list of 290 genes. Variant prioritization was discussed in a multidisciplinary team based on genotype-phenotype correlation, and segregation studies were performed with available family members.

Results The study identified 22 candidate variants in 17 out of 18 patients (94%). Eleven patients had complete genotype-phenotype correlation, resulting in a diagnostic yield of 61%, 5 (28%) were classified as partially solved, and 2 (11%) remained unsolved. Variants were identified in platelet (ACTN1, ANKRD26, CYCS, GATA1, GFI1B, ITGA2, NBEAL2, RUNX1, SRC, TUBB1), bleeding (APOLD1), and coagulation (F7, F8, F11, VWF) genes. Notably, 9 out of 22 (41%) variants were previously unreported. Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics guidelines and reclassification of three variants based on family segregation evidence, resulting in the identification of 10 pathogenic or likely pathogenic variants, 6 variants of uncertain significance, and 6 benign or likely benign variants.

Conclusion This study demonstrated the high potential of WES in identifying rare molecular defects causing IBD in pediatric patients, improving their management, prognosis, and treatment, particularly for patients at risk of malignancy and/or bleeding due to invasive procedures.

Keywords

whole-exome sequencing - next-generation sequencing - inherited bleeding disorders - genotype-phenotype correlation - thrombocytopenia - children cohort

Supplementary Material



Publication History

Received: 07 June 2023

Accepted: 30 November 2023

Article published online:
29 December 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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