Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency
Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) caused by SERPING1 mutations is a rare monogenic disorder characterized by a high frequency of de novo mutations, allelic heterogeneity and populational differences. Geno- and phenotype correlation data are limited. Addres...
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doaj-d7482aa23eae498086d951f1872d22f12021-09-05T14:01:31ZengSciendoRomanian Journal of Laboratory Medicine2284-56232019-07-0127325526710.2478/rrlm-2019-0029rrlm-2019-0029Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiencyGábos Gabriella0Moldovan Dumitru1Dobru Daniela2Mihály Enikő3Bara Noémi4Nădășan Valentin5Hutanu Adina6Csép Katalin7Lotus Life Clinic, Târgu Mureș, RomaniaRomanian Network for Hereditary Angioedema, RomaniaUniversity of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, RomaniaRomanian Network for Hereditary Angioedema, RomaniaRomanian Network for Hereditary Angioedema, RomaniaRomanian Network for Hereditary Angioedema, RomaniaCenter for Advanced Medical and Pharmaceutical Research, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, RomaniaGenetics Department, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, RomaniaBackground: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) caused by SERPING1 mutations is a rare monogenic disorder characterized by a high frequency of de novo mutations, allelic heterogeneity and populational differences. Geno- and phenotype correlation data are limited. Addressing the pathogenic complexity, we proposed to analyze the clinical and genetic characteristics in a set of Romanian patients. Material and Methods: 49 patients from 22 unrelated families with C1-INH-HAE were investigated, by calculating clinical severity score (CSS), C1-INH and C4 level assessment by nephelometric assays, C1-INH function study by functional enzyme-linked immunosorbent assay, and mutation analysis by sequencing and MLPA. Clinical manifestations by missense vs other mutation mechanisms were compared. Results: The mean age at diagnosis and onset was 28.8±14.7 and 15.1±15.2 years, while the diagnostic delay 13.1±10.1 years. CSS ranged from 2 to 9, with a mean of 5.4±1.8. The frequency of missense and nonsense mutations, splice defects, frameshift mutations and large gene rearrangements was 61.22, 6.12, 22.4, 6.12 and 4.08%; in the regulatory sequence no mutation was described. In type II, only missense mutations were noted. Lower levels of C1-INH characterized index cases caused by mechanisms other than missense mutation, with more severe consequences on protein synthesis (p=0.017). 53% of the cases were identified by familial screening. Conclusion: A later onset of disease manifestations and a higher frequency of missense mutations characterize HAE in Romanian patients with SERPING1 mutation. Genetic analysis improves the management of affected families, and may inform about disease severity.https://doi.org/10.2478/rrlm-2019-0029hereditary angioedemac1 inhibitor deficiencyserping1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gábos Gabriella Moldovan Dumitru Dobru Daniela Mihály Enikő Bara Noémi Nădășan Valentin Hutanu Adina Csép Katalin |
spellingShingle |
Gábos Gabriella Moldovan Dumitru Dobru Daniela Mihály Enikő Bara Noémi Nădășan Valentin Hutanu Adina Csép Katalin Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency Romanian Journal of Laboratory Medicine hereditary angioedema c1 inhibitor deficiency serping1 |
author_facet |
Gábos Gabriella Moldovan Dumitru Dobru Daniela Mihály Enikő Bara Noémi Nădășan Valentin Hutanu Adina Csép Katalin |
author_sort |
Gábos Gabriella |
title |
Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency |
title_short |
Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency |
title_full |
Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency |
title_fullStr |
Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency |
title_full_unstemmed |
Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency |
title_sort |
mutational spectrum and genotype-phenotype relationships in a cohort of romanian hereditary angioedema patients caused by c1 inhibitor deficiency |
publisher |
Sciendo |
series |
Romanian Journal of Laboratory Medicine |
issn |
2284-5623 |
publishDate |
2019-07-01 |
description |
Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) caused by SERPING1 mutations is a rare monogenic disorder characterized by a high frequency of de novo mutations, allelic heterogeneity and populational differences. Geno- and phenotype correlation data are limited. Addressing the pathogenic complexity, we proposed to analyze the clinical and genetic characteristics in a set of Romanian patients. Material and Methods: 49 patients from 22 unrelated families with C1-INH-HAE were investigated, by calculating clinical severity score (CSS), C1-INH and C4 level assessment by nephelometric assays, C1-INH function study by functional enzyme-linked immunosorbent assay, and mutation analysis by sequencing and MLPA. Clinical manifestations by missense vs other mutation mechanisms were compared. Results: The mean age at diagnosis and onset was 28.8±14.7 and 15.1±15.2 years, while the diagnostic delay 13.1±10.1 years. CSS ranged from 2 to 9, with a mean of 5.4±1.8. The frequency of missense and nonsense mutations, splice defects, frameshift mutations and large gene rearrangements was 61.22, 6.12, 22.4, 6.12 and 4.08%; in the regulatory sequence no mutation was described. In type II, only missense mutations were noted. Lower levels of C1-INH characterized index cases caused by mechanisms other than missense mutation, with more severe consequences on protein synthesis (p=0.017). 53% of the cases were identified by familial screening. Conclusion: A later onset of disease manifestations and a higher frequency of missense mutations characterize HAE in Romanian patients with SERPING1 mutation. Genetic analysis improves the management of affected families, and may inform about disease severity. |
topic |
hereditary angioedema c1 inhibitor deficiency serping1 |
url |
https://doi.org/10.2478/rrlm-2019-0029 |
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