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Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing

ESSENTIALS: The differential diagnosis of acute thrombotic microangiopathy (TMA) is challenging. To the ADAMTS13 activity < or >10% was added a next‐generation sequencing (NGS) gene panel. The ADAMTS13 mutation p.Cys754Arg was frequent in hereditary thrombotic thrombocytopenic purpura. We iden...

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Autores principales: Fidalgo, Teresa, Martinho, Patrícia, Pinto, Catarina S., Oliveira, Ana C., Salvado, Ramon, Borràs, Nina, Coucelo, Margarida, Manco, Licínio, Maia, Tabita, Mendes, M. João, Del Orbe Barreto, Rafael, Corrales, Irene, Vidal, Francisco, Ribeiro, M. Letícia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058207/
https://www.ncbi.nlm.nih.gov/pubmed/30046676
http://dx.doi.org/10.1002/rth2.12016
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author Fidalgo, Teresa
Martinho, Patrícia
Pinto, Catarina S.
Oliveira, Ana C.
Salvado, Ramon
Borràs, Nina
Coucelo, Margarida
Manco, Licínio
Maia, Tabita
Mendes, M. João
Del Orbe Barreto, Rafael
Corrales, Irene
Vidal, Francisco
Ribeiro, M. Letícia
author_facet Fidalgo, Teresa
Martinho, Patrícia
Pinto, Catarina S.
Oliveira, Ana C.
Salvado, Ramon
Borràs, Nina
Coucelo, Margarida
Manco, Licínio
Maia, Tabita
Mendes, M. João
Del Orbe Barreto, Rafael
Corrales, Irene
Vidal, Francisco
Ribeiro, M. Letícia
author_sort Fidalgo, Teresa
collection PubMed
description ESSENTIALS: The differential diagnosis of acute thrombotic microangiopathy (TMA) is challenging. To the ADAMTS13 activity < or >10% was added a next‐generation sequencing (NGS) gene panel. The ADAMTS13 mutation p.Cys754Arg was frequent in hereditary thrombotic thrombocytopenic purpura. We identified novel complement gene mutations and this procedure improved our diagnostic strategy. BACKGROUND: The 2 main forms of thrombotic microangiopathy (TMA) are thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). Deficiency of ADAMTS13 and dysregulation of the complement pathway result in TTP and aHUS, respectively; however, overlap of their clinical characteristics makes differential diagnosis challenging. OBJECTIVES AND METHODS: We aimed to develop a TMA diagnosis workflow based on ADAMTS13 activity and screening of ADAMTS13 and complement genes using a custom next‐generation sequencing (NGS) gene panel. PATIENTS: For this, from a cohort of 154 Portuguese patients with acute TMA, the genotype‐phenotype correlations were analyzed in 7 hereditary TTP (ADAMTS13 activity <10%, no inhibitor), 36 acquired TTP (ADAMTS13 activity <10%, presence of an inhibitor), and in 34 presumable aHUS. RESULTS: In total, 37 different rare variants, 8 of which novel (in ADAMTS13,CFH, and CD46), were identified across 7 genes. Thirteen TTP patients were homozygous (n=6), compound heterozygous (n=2), and heterozygous (n=5) for 11 ADAMTS13 variants (6 pathogenic mutations). Among the 34 aHUS patients, 17 were heterozygous for 23 variants in the different complement genes with distinct consequences, ranging from single pathogenic mutations associated with complete disease penetrance to benign variants that cause aHUS only when combined with other variants and/or CFH and CD46 risk haplotypes or CFHR1‐3 deletion. CONCLUSIONS: Our study provides evidence of the usefulness of the NGS panel as an excellent technology that enables more rapid diagnosis of TMA, and is a valuable asset in clinical practice to discriminate between TTP and aHUS.
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spelling pubmed-60582072018-07-25 Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing Fidalgo, Teresa Martinho, Patrícia Pinto, Catarina S. Oliveira, Ana C. Salvado, Ramon Borràs, Nina Coucelo, Margarida Manco, Licínio Maia, Tabita Mendes, M. João Del Orbe Barreto, Rafael Corrales, Irene Vidal, Francisco Ribeiro, M. Letícia Res Pract Thromb Haemost Original Articles ESSENTIALS: The differential diagnosis of acute thrombotic microangiopathy (TMA) is challenging. To the ADAMTS13 activity < or >10% was added a next‐generation sequencing (NGS) gene panel. The ADAMTS13 mutation p.Cys754Arg was frequent in hereditary thrombotic thrombocytopenic purpura. We identified novel complement gene mutations and this procedure improved our diagnostic strategy. BACKGROUND: The 2 main forms of thrombotic microangiopathy (TMA) are thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). Deficiency of ADAMTS13 and dysregulation of the complement pathway result in TTP and aHUS, respectively; however, overlap of their clinical characteristics makes differential diagnosis challenging. OBJECTIVES AND METHODS: We aimed to develop a TMA diagnosis workflow based on ADAMTS13 activity and screening of ADAMTS13 and complement genes using a custom next‐generation sequencing (NGS) gene panel. PATIENTS: For this, from a cohort of 154 Portuguese patients with acute TMA, the genotype‐phenotype correlations were analyzed in 7 hereditary TTP (ADAMTS13 activity <10%, no inhibitor), 36 acquired TTP (ADAMTS13 activity <10%, presence of an inhibitor), and in 34 presumable aHUS. RESULTS: In total, 37 different rare variants, 8 of which novel (in ADAMTS13,CFH, and CD46), were identified across 7 genes. Thirteen TTP patients were homozygous (n=6), compound heterozygous (n=2), and heterozygous (n=5) for 11 ADAMTS13 variants (6 pathogenic mutations). Among the 34 aHUS patients, 17 were heterozygous for 23 variants in the different complement genes with distinct consequences, ranging from single pathogenic mutations associated with complete disease penetrance to benign variants that cause aHUS only when combined with other variants and/or CFH and CD46 risk haplotypes or CFHR1‐3 deletion. CONCLUSIONS: Our study provides evidence of the usefulness of the NGS panel as an excellent technology that enables more rapid diagnosis of TMA, and is a valuable asset in clinical practice to discriminate between TTP and aHUS. John Wiley and Sons Inc. 2017-06-23 /pmc/articles/PMC6058207/ /pubmed/30046676 http://dx.doi.org/10.1002/rth2.12016 Text en © 2017 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Fidalgo, Teresa
Martinho, Patrícia
Pinto, Catarina S.
Oliveira, Ana C.
Salvado, Ramon
Borràs, Nina
Coucelo, Margarida
Manco, Licínio
Maia, Tabita
Mendes, M. João
Del Orbe Barreto, Rafael
Corrales, Irene
Vidal, Francisco
Ribeiro, M. Letícia
Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing
title Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing
title_full Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing
title_fullStr Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing
title_full_unstemmed Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing
title_short Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing
title_sort combined study of adamts13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058207/
https://www.ncbi.nlm.nih.gov/pubmed/30046676
http://dx.doi.org/10.1002/rth2.12016
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