Publicação
Congenital antithrombin and prekallikrein deficiency: genetic and phenotypic study of variants in the SERPINC1 and KLKB1 genes
| Resumo: | Hereditary antithrombin (AT) deficiency is a major thrombophilic disorder, conferring moderate to high risk of venous thromboembolism (VTE). Its clinical heterogeneity often complicates diagnosis and may lead to underestimation by conventional functional assays. In contrast, congenital prekallikrein (PK) deficiency causes marked prolongation of activated partial thromboplastin time (aPTT) without bleeding manifestations, which can be misinterpreted as a severe coagulation defect. In both conditions, these limitations underscore the value of genetic analysis for definitive diagnosis and characterization. This study performed genetic analysis of patients with suspected AT (SERPINC1) and PK (KLKB1) deficiencies to clarify diagnosis, establish genotype–phenotype correlations, and assess the clinical impact of identified variants. Among 176 individuals referred for SERPINC1 testing, 39 probands carried 19 distinct variants, predominantly heterozygous, including eight novel variants. Classification according to ACMG criteria and assignment of deficiency type enabled thrombotic risk stratification. Family studies identified asymptomatic carriers and confirmed segregation in six families. For PK, PCR/Sanger sequencing identified five pathogenic or likely pathogenic KLKB1 variants in four patients with prolonged aPTT but no bleeding history, explaining laboratory abnormalities and excluding other coagulopathies. These findings highlight the critical role of molecular characterization in hereditary thrombophilia and in laboratory anomalies without clinical expression. Genetic testing improves diagnostic accuracy, informs prophylactic and therapeutic decisions, and provides essential information for genetic counseling and interpretation of coagulation assays. |
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| Autores principais: | Carvão, Sofia Pereira Nunes da Silva |
| Assunto: | Congenital antithrombin deficiency Congenital prekallikrein deficiency Genetic study Genotype-phenotype SERPINC1 KLKB1 |
| Ano: | 2025 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Aveiro |
| Idioma: | inglês |
| Origem: | RIA - Repositório Institucional da Universidade de Aveiro |
| Resumo: | Hereditary antithrombin (AT) deficiency is a major thrombophilic disorder, conferring moderate to high risk of venous thromboembolism (VTE). Its clinical heterogeneity often complicates diagnosis and may lead to underestimation by conventional functional assays. In contrast, congenital prekallikrein (PK) deficiency causes marked prolongation of activated partial thromboplastin time (aPTT) without bleeding manifestations, which can be misinterpreted as a severe coagulation defect. In both conditions, these limitations underscore the value of genetic analysis for definitive diagnosis and characterization. This study performed genetic analysis of patients with suspected AT (SERPINC1) and PK (KLKB1) deficiencies to clarify diagnosis, establish genotype–phenotype correlations, and assess the clinical impact of identified variants. Among 176 individuals referred for SERPINC1 testing, 39 probands carried 19 distinct variants, predominantly heterozygous, including eight novel variants. Classification according to ACMG criteria and assignment of deficiency type enabled thrombotic risk stratification. Family studies identified asymptomatic carriers and confirmed segregation in six families. For PK, PCR/Sanger sequencing identified five pathogenic or likely pathogenic KLKB1 variants in four patients with prolonged aPTT but no bleeding history, explaining laboratory abnormalities and excluding other coagulopathies. These findings highlight the critical role of molecular characterization in hereditary thrombophilia and in laboratory anomalies without clinical expression. Genetic testing improves diagnostic accuracy, informs prophylactic and therapeutic decisions, and provides essential information for genetic counseling and interpretation of coagulation assays. |
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