CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort

Detalhes bibliográficos
Autor(a) principal: Santos-Silva, R
Data de Publicação: 2019
Outros Autores: Cardoso, R, Lopes, L, Fonseca, M, Espada, F, Sampaio, L, Brandão, C, Antunes, A, Bragança, G, et al.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.10/2373
Resumo: BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype-phenotype correlation. METHODS: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype-phenotype correlation. RESULTS: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients' stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype-phenotype correlation (80%). CONCLUSION: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype-phenotype correlation observed.
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spelling CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric CohortCongenital adrenal hyperplasiaChildPhenotypePortugalBACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype-phenotype correlation. METHODS: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype-phenotype correlation. RESULTS: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients' stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype-phenotype correlation (80%). CONCLUSION: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype-phenotype correlation observed.Karger PublishersRepositório do Hospital Prof. Doutor Fernando FonsecaSantos-Silva, RCardoso, RLopes, LFonseca, MEspada, FSampaio, LBrandão, CAntunes, ABragança, G, et al.2019-12-23T10:59:30Z2019-01-01T00:00:00Z2019-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.10/2373engHorm Res Paediatr. 2019;91(1):33-451663-282610.1159/000497485metadata only accessinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-09-20T15:53:03Zoai:repositorio.hff.min-saude.pt:10400.10/2373Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T15:53:18.921248Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
title CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
spellingShingle CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
Santos-Silva, R
Congenital adrenal hyperplasia
Child
Phenotype
Portugal
title_short CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
title_full CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
title_fullStr CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
title_full_unstemmed CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
title_sort CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
author Santos-Silva, R
author_facet Santos-Silva, R
Cardoso, R
Lopes, L
Fonseca, M
Espada, F
Sampaio, L
Brandão, C
Antunes, A
Bragança, G, et al.
author_role author
author2 Cardoso, R
Lopes, L
Fonseca, M
Espada, F
Sampaio, L
Brandão, C
Antunes, A
Bragança, G, et al.
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório do Hospital Prof. Doutor Fernando Fonseca
dc.contributor.author.fl_str_mv Santos-Silva, R
Cardoso, R
Lopes, L
Fonseca, M
Espada, F
Sampaio, L
Brandão, C
Antunes, A
Bragança, G, et al.
dc.subject.por.fl_str_mv Congenital adrenal hyperplasia
Child
Phenotype
Portugal
topic Congenital adrenal hyperplasia
Child
Phenotype
Portugal
description BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype-phenotype correlation. METHODS: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype-phenotype correlation. RESULTS: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients' stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype-phenotype correlation (80%). CONCLUSION: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype-phenotype correlation observed.
publishDate 2019
dc.date.none.fl_str_mv 2019-12-23T10:59:30Z
2019-01-01T00:00:00Z
2019-01-01T00:00:00Z
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/10400.10/2373
url http://hdl.handle.net/10400.10/2373
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Horm Res Paediatr. 2019;91(1):33-45
1663-2826
10.1159/000497485
dc.rights.driver.fl_str_mv metadata only access
info:eu-repo/semantics/openAccess
rights_invalid_str_mv metadata only access
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Karger Publishers
publisher.none.fl_str_mv Karger Publishers
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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