Comprehensive Screening of Genetic Variants in the Coding Region of F8 in Severe Hemophilia A Reveals a Relationship with Disease Severity in a Colombian Cohort.

Autor: Sarmiento Doncel S; Integral Solutions SD SAS, Integral Solutions Research, Bogota 110121, Colombia.; Life Sciences and Health Research Group, Graduates School, CES University, Medellin 050021, Colombia.; Doctoral School, Catholic University of Valencia San Vicente Mártir (UCV), 46002 Valencia, Spain., Peláez RG; Life Sciences and Health Research Group, Graduates School, CES University, Medellin 050021, Colombia., Lapunzina P; Instituto de Genética Médica y Molecular (INGEMM), IdiPaz, Hospital Universitario La Paz, 28046 Madrid, Spain.; CIBERER, Centro de Investigación en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28029 Madrid, Spain.; ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 75019 Paris, France., Corrales-Medina FF; Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Miami-Miller School of Medicine, Miami, FL 33136, USA.; University of Miami-Hemophilia Treatment Center, Miami, FL 33136, USA., Díaz Mosquera GA; Integral Solutions SD SAS, Integral Solutions Research, Bogota 110121, Colombia., Bonanad S; Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain., Cortes JM; Integral Solutions SD SAS, Integral Solutions Research, Bogota 110121, Colombia., Cazalla M; Instituto de Genética Médica y Molecular (INGEMM), IdiPaz, Hospital Universitario La Paz, 28046 Madrid, Spain.; CIBERER, Centro de Investigación en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28029 Madrid, Spain., Gallego N; Instituto de Genética Médica y Molecular (INGEMM), IdiPaz, Hospital Universitario La Paz, 28046 Madrid, Spain.; CIBERER, Centro de Investigación en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28029 Madrid, Spain.; ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 75019 Paris, France., Querol-Giner F; Physiotherapy in Motion Multispeciality Research Group (PTinMOTION), Department of Physiotherapy, University of Valencia, 46010 Valencia, Spain., Tenorio J; Instituto de Genética Médica y Molecular (INGEMM), IdiPaz, Hospital Universitario La Paz, 28046 Madrid, Spain.; CIBERER, Centro de Investigación en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28029 Madrid, Spain.; ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 75019 Paris, France.; BITGENETIC LAB, Qube Technology Park, Tres Cantos, 28460 Madrid, Spain., López Guerrero JA; Doctoral School, Catholic University of Valencia San Vicente Mártir (UCV), 46002 Valencia, Spain.; Department of Pathology, Medical School, Catholic University of Valencia, San Vicente Martir, 46010 Valencia, Spain.; Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain.
Jazyk: angličtina
Zdroj: Life (Basel, Switzerland) [Life (Basel)] 2024 Aug 21; Vol. 14 (8). Date of Electronic Publication: 2024 Aug 21.
DOI: 10.3390/life14081041
Abstrakt: Hemophilia A is an X-linked disorder characterized by quantitative deficiency of coagulation factor VIII (FVIII) caused by pathogenic variants in the factor 8 ( F8 ) gene. Our study's primary objective was to identify genetic variants within the exonic region of F8 in 50 Colombian male participants with severe hemophilia A (HA). Whole-exome sequencing and bioinformatics analyses were performed, and bivariate analysis was used to evaluate the relationship between identified variants, disease severity, and inhibitor risk formation. Out of the 50 participants, 21 were found to have 17 different pathogenic F8 variants (var). It was found that 70% (var = 12) of them were premature truncation variants (nonsense, frameshift), 17.6% (var = 3) were missense mutations, and 11.7% (var = 2) were splice-site variants. Interestingly, 35% (var = 6) of the identified variants have not been previously reported in the literature. All patients with a history of positive inhibitors (n = 4) were found to have high-impact genetic variants (nonsense and frameshift). When investigating the relationship between variant location (heavy versus light chain) and specific inhibitor risk, 75% (n = 3) of the inhibitor participants were found to have variants located in the F8 light chain ( p = 0.075), suggesting that conserved domains are associated with higher inhibitor risk. In summary, we identified genetic variants within the F8 that can possibly influence inhibitor development in Colombian patients with severe HA. Our results provide a basis for future studies and the development of further personalized treatment strategies in this population.
Databáze: MEDLINE
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