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Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome
Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibili...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224898/ https://www.ncbi.nlm.nih.gov/pubmed/34125832 http://dx.doi.org/10.1371/journal.pntd.0009507 |
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author | Borda, Victor da Silva Francisco Junior, Ronaldo Carvalho, Joseane B. Morais, Guilherme L. Duque Rossi, Átila Pezzuto, Paula Azevedo, Girlene S. Schamber-Reis, Bruno L. Portari, Elyzabeth A. Melo, Adriana Moreira, Maria Elisabeth L. Guida, Letícia C. Cunha, Daniela P. Gomes, Leonardo Vasconcelos, Zilton F. M. Faucz, Fabio R. Tanuri, Amilcar Stratakis, Constantine A. Aguiar, Renato S. Cardoso, Cynthia Chester de Vasconcelos, Ana Tereza Ribeiro |
author_facet | Borda, Victor da Silva Francisco Junior, Ronaldo Carvalho, Joseane B. Morais, Guilherme L. Duque Rossi, Átila Pezzuto, Paula Azevedo, Girlene S. Schamber-Reis, Bruno L. Portari, Elyzabeth A. Melo, Adriana Moreira, Maria Elisabeth L. Guida, Letícia C. Cunha, Daniela P. Gomes, Leonardo Vasconcelos, Zilton F. M. Faucz, Fabio R. Tanuri, Amilcar Stratakis, Constantine A. Aguiar, Renato S. Cardoso, Cynthia Chester de Vasconcelos, Ana Tereza Ribeiro |
author_sort | Borda, Victor |
collection | PubMed |
description | Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibility and response to ZIKV infection may be related to the virus itself, the environment, and maternal genetic background. Nevertheless, the newborn’s genetic contribution to the critical illness is still not elucidated. Here, we aimed to identify possible genetic variants as well as relevant biological pathways that might be associated with CZS phenotypes. For this purpose, we performed a whole-exome sequencing in 40 children born to women with confirmed exposure to ZIKV during pregnancy. We investigated the occurrence of rare harmful single-nucleotide variants (SNVs) possibly associated with inborn errors in genes ontologically related to CZS phenotypes. Moreover, an exome-wide association analysis was also performed using a case-control design (29 CZS cases and 11 controls), for both common and rare variants. Five out of the 29 CZS patients harbored known pathogenic variants likely to contribute to mild to severe manifestations observed. Approximately, 30% of affected individuals carried at least one pathogenic or likely pathogenic SNV in genes candidates to play a role in CZS. Our common variant association analysis detected a suggestive protective effect of the rs2076469 in DISP3 gene (p-value: 1.39 x 10(−5)). The IL12RB2 gene (p-value: 2.18x10(-11)) also showed an unusual distribution of nonsynonymous rare SNVs in control samples. Finally, genes harboring harmful variants are involved in processes related to CZS phenotypes such as neurological development and immunity. Therefore, both rare and common variations may be likely to contribute as the underlying genetic cause of CZS susceptibility. The variations and pathways identified in this study may also have implications for the development of therapeutic strategies in the future. |
format | Online Article Text |
id | pubmed-8224898 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-82248982021-07-21 Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome Borda, Victor da Silva Francisco Junior, Ronaldo Carvalho, Joseane B. Morais, Guilherme L. Duque Rossi, Átila Pezzuto, Paula Azevedo, Girlene S. Schamber-Reis, Bruno L. Portari, Elyzabeth A. Melo, Adriana Moreira, Maria Elisabeth L. Guida, Letícia C. Cunha, Daniela P. Gomes, Leonardo Vasconcelos, Zilton F. M. Faucz, Fabio R. Tanuri, Amilcar Stratakis, Constantine A. Aguiar, Renato S. Cardoso, Cynthia Chester de Vasconcelos, Ana Tereza Ribeiro PLoS Negl Trop Dis Research Article Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibility and response to ZIKV infection may be related to the virus itself, the environment, and maternal genetic background. Nevertheless, the newborn’s genetic contribution to the critical illness is still not elucidated. Here, we aimed to identify possible genetic variants as well as relevant biological pathways that might be associated with CZS phenotypes. For this purpose, we performed a whole-exome sequencing in 40 children born to women with confirmed exposure to ZIKV during pregnancy. We investigated the occurrence of rare harmful single-nucleotide variants (SNVs) possibly associated with inborn errors in genes ontologically related to CZS phenotypes. Moreover, an exome-wide association analysis was also performed using a case-control design (29 CZS cases and 11 controls), for both common and rare variants. Five out of the 29 CZS patients harbored known pathogenic variants likely to contribute to mild to severe manifestations observed. Approximately, 30% of affected individuals carried at least one pathogenic or likely pathogenic SNV in genes candidates to play a role in CZS. Our common variant association analysis detected a suggestive protective effect of the rs2076469 in DISP3 gene (p-value: 1.39 x 10(−5)). The IL12RB2 gene (p-value: 2.18x10(-11)) also showed an unusual distribution of nonsynonymous rare SNVs in control samples. Finally, genes harboring harmful variants are involved in processes related to CZS phenotypes such as neurological development and immunity. Therefore, both rare and common variations may be likely to contribute as the underlying genetic cause of CZS susceptibility. The variations and pathways identified in this study may also have implications for the development of therapeutic strategies in the future. Public Library of Science 2021-06-14 /pmc/articles/PMC8224898/ /pubmed/34125832 http://dx.doi.org/10.1371/journal.pntd.0009507 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Borda, Victor da Silva Francisco Junior, Ronaldo Carvalho, Joseane B. Morais, Guilherme L. Duque Rossi, Átila Pezzuto, Paula Azevedo, Girlene S. Schamber-Reis, Bruno L. Portari, Elyzabeth A. Melo, Adriana Moreira, Maria Elisabeth L. Guida, Letícia C. Cunha, Daniela P. Gomes, Leonardo Vasconcelos, Zilton F. M. Faucz, Fabio R. Tanuri, Amilcar Stratakis, Constantine A. Aguiar, Renato S. Cardoso, Cynthia Chester de Vasconcelos, Ana Tereza Ribeiro Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome |
title | Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome |
title_full | Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome |
title_fullStr | Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome |
title_full_unstemmed | Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome |
title_short | Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome |
title_sort | whole-exome sequencing reveals insights into genetic susceptibility to congenital zika syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224898/ https://www.ncbi.nlm.nih.gov/pubmed/34125832 http://dx.doi.org/10.1371/journal.pntd.0009507 |
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