Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome
Autor(a) principal: | |
---|---|
Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | https://doi.org/10.1371/journal.pntd.0009507 http://hdl.handle.net/1843/56416 https://orcid.org/0000-0003-3209-3961 https://orcid.org/0000-0002-8575-544X https://orcid.org/0000-0002-2034-0294 https://orcid.org/0000-0003-3543-1532 https://orcid.org/0000-0002-1721-0608 https://orcid.org/0000-0002-2193-2224 https://orcid.org/0000-0001-7959-9842 https://orcid.org/0000-0003-0570-750X https://orcid.org/0000-0002-4058-5520 https://orcid.org/0000-0001-5180-3717 https://orcid.org/0000-0003-0565-7047 https://orcid.org/0000-0001-6235-8807 https://orcid.org/0000-0001-9570-8244 https://orcid.org/0000-0002-7640-1463 https://orcid.org/0000-0003-2372-0898 |
Resumo: | 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. |
id |
UFMG_6820c028eda571116ee21e146b9970fe |
---|---|
oai_identifier_str |
oai:repositorio.ufmg.br:1843/56416 |
network_acronym_str |
UFMG |
network_name_str |
Repositório Institucional da UFMG |
repository_id_str |
|
spelling |
2023-07-17T18:03:00Z2023-07-17T18:03:00Z2021156117https://doi.org/10.1371/journal.pntd.00095071935-2735http://hdl.handle.net/1843/56416https://orcid.org/0000-0003-3209-3961https://orcid.org/0000-0002-8575-544Xhttps://orcid.org/0000-0002-2034-0294https://orcid.org/0000-0003-3543-1532https://orcid.org/0000-0002-1721-0608https://orcid.org/0000-0002-2193-2224https://orcid.org/0000-0001-7959-9842https://orcid.org/0000-0003-0570-750Xhttps://orcid.org/0000-0002-4058-5520https://orcid.org/0000-0001-5180-3717https://orcid.org/0000-0003-0565-7047https://orcid.org/0000-0001-6235-8807https://orcid.org/0000-0001-9570-8244https://orcid.org/0000-0002-7640-1463https://orcid.org/0000-0003-2372-0898https://orcid.org/0000-0003-2372-0898Congenital 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.porUniversidade Federal de Minas GeraisUFMGBrasilICB - INSTITUTO DE CIÊNCIAS BIOLOGICASPLOS Neglected Tropical DiseasesVírus da ZikaZikaGeneticWhole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndromeinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttps://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0009507Victor BordaAdriana MeloMaria Elisabeth MoreiraLetícia GuidaDaniela P. CunhaLeonardo GomesZilton VasconcelosFabio FauczAmilcar TanuriConstantine StratakisRenato Santana de AguiarRonaldo da Silva Francisco JuniorCynthia Chester CardosoAna Tereza Ribeiro de VasconcelosJoseane B. CarvalhoGuilherme L. MoraisÁtila Duque RossiPaula PezzutoGirlene S. AzevedoBruno Luiz Fonseca Schamber-ReisElyzabeth Avvad Portariinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGLICENSELicense.txtLicense.txttext/plain; charset=utf-82042https://repositorio.ufmg.br/bitstream/1843/56416/1/License.txtfa505098d172de0bc8864fc1287ffe22MD51ORIGINALWhole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome.pdfWhole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome.pdfapplication/pdf40823351https://repositorio.ufmg.br/bitstream/1843/56416/2/Whole-exome%20sequencing%20reveals%20insights%20into%20genetic%20susceptibility%20to%20Congenital%20Zika%20Syndrome.pdfd49959cca37c3be5faba5e10ee011c53MD521843/564162023-07-17 15:03:00.187oai:repositorio.ufmg.br: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Repositório de PublicaçõesPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-07-17T18:03Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.pt_BR.fl_str_mv |
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 |
spellingShingle |
Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome Victor Borda Zika Genetic Vírus da Zika |
title_short |
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_sort |
Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome |
author |
Victor Borda |
author_facet |
Victor Borda Adriana Melo Maria Elisabeth Moreira Letícia Guida Daniela P. Cunha Leonardo Gomes Zilton Vasconcelos Fabio Faucz Amilcar Tanuri Constantine Stratakis Renato Santana de Aguiar Ronaldo da Silva Francisco Junior Cynthia Chester Cardoso Ana Tereza Ribeiro de Vasconcelos Joseane B. Carvalho Guilherme L. Morais Átila Duque Rossi Paula Pezzuto Girlene S. Azevedo Bruno Luiz Fonseca Schamber-Reis Elyzabeth Avvad Portari |
author_role |
author |
author2 |
Adriana Melo Maria Elisabeth Moreira Letícia Guida Daniela P. Cunha Leonardo Gomes Zilton Vasconcelos Fabio Faucz Amilcar Tanuri Constantine Stratakis Renato Santana de Aguiar Ronaldo da Silva Francisco Junior Cynthia Chester Cardoso Ana Tereza Ribeiro de Vasconcelos Joseane B. Carvalho Guilherme L. Morais Átila Duque Rossi Paula Pezzuto Girlene S. Azevedo Bruno Luiz Fonseca Schamber-Reis Elyzabeth Avvad Portari |
author2_role |
author author author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Victor Borda Adriana Melo Maria Elisabeth Moreira Letícia Guida Daniela P. Cunha Leonardo Gomes Zilton Vasconcelos Fabio Faucz Amilcar Tanuri Constantine Stratakis Renato Santana de Aguiar Ronaldo da Silva Francisco Junior Cynthia Chester Cardoso Ana Tereza Ribeiro de Vasconcelos Joseane B. Carvalho Guilherme L. Morais Átila Duque Rossi Paula Pezzuto Girlene S. Azevedo Bruno Luiz Fonseca Schamber-Reis Elyzabeth Avvad Portari |
dc.subject.por.fl_str_mv |
Zika Genetic |
topic |
Zika Genetic Vírus da Zika |
dc.subject.other.pt_BR.fl_str_mv |
Vírus da Zika |
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. |
publishDate |
2021 |
dc.date.issued.fl_str_mv |
2021 |
dc.date.accessioned.fl_str_mv |
2023-07-17T18:03:00Z |
dc.date.available.fl_str_mv |
2023-07-17T18:03:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1843/56416 |
dc.identifier.doi.pt_BR.fl_str_mv |
https://doi.org/10.1371/journal.pntd.0009507 |
dc.identifier.issn.pt_BR.fl_str_mv |
1935-2735 |
dc.identifier.orcid.pt_BR.fl_str_mv |
https://orcid.org/0000-0003-3209-3961 https://orcid.org/0000-0002-8575-544X https://orcid.org/0000-0002-2034-0294 https://orcid.org/0000-0003-3543-1532 https://orcid.org/0000-0002-1721-0608 https://orcid.org/0000-0002-2193-2224 https://orcid.org/0000-0001-7959-9842 https://orcid.org/0000-0003-0570-750X https://orcid.org/0000-0002-4058-5520 https://orcid.org/0000-0001-5180-3717 https://orcid.org/0000-0003-0565-7047 https://orcid.org/0000-0001-6235-8807 https://orcid.org/0000-0001-9570-8244 https://orcid.org/0000-0002-7640-1463 https://orcid.org/0000-0003-2372-0898 https://orcid.org/0000-0003-2372-0898 |
url |
https://doi.org/10.1371/journal.pntd.0009507 http://hdl.handle.net/1843/56416 https://orcid.org/0000-0003-3209-3961 https://orcid.org/0000-0002-8575-544X https://orcid.org/0000-0002-2034-0294 https://orcid.org/0000-0003-3543-1532 https://orcid.org/0000-0002-1721-0608 https://orcid.org/0000-0002-2193-2224 https://orcid.org/0000-0001-7959-9842 https://orcid.org/0000-0003-0570-750X https://orcid.org/0000-0002-4058-5520 https://orcid.org/0000-0001-5180-3717 https://orcid.org/0000-0003-0565-7047 https://orcid.org/0000-0001-6235-8807 https://orcid.org/0000-0001-9570-8244 https://orcid.org/0000-0002-7640-1463 https://orcid.org/0000-0003-2372-0898 |
identifier_str_mv |
1935-2735 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.ispartof.pt_BR.fl_str_mv |
PLOS Neglected Tropical Diseases |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
dc.publisher.initials.fl_str_mv |
UFMG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
ICB - INSTITUTO DE CIÊNCIAS BIOLOGICAS |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
instname_str |
Universidade Federal de Minas Gerais (UFMG) |
instacron_str |
UFMG |
institution |
UFMG |
reponame_str |
Repositório Institucional da UFMG |
collection |
Repositório Institucional da UFMG |
bitstream.url.fl_str_mv |
https://repositorio.ufmg.br/bitstream/1843/56416/1/License.txt https://repositorio.ufmg.br/bitstream/1843/56416/2/Whole-exome%20sequencing%20reveals%20insights%20into%20genetic%20susceptibility%20to%20Congenital%20Zika%20Syndrome.pdf |
bitstream.checksum.fl_str_mv |
fa505098d172de0bc8864fc1287ffe22 d49959cca37c3be5faba5e10ee011c53 |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
repository.mail.fl_str_mv |
|
_version_ |
1803589470786682880 |