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CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort.
Horm Res Paediatr. 2019; 91(1):33-45.HR

Abstract

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.

Authors+Show Affiliations

Department of Pediatric Endocrinology,<bold></bold> Centro Hospitalar Universitário de S. João, Porto, Portugal, ritasantossilva@gmail.com.Department of Pediatric Endocrinology, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.Department of Pediatric Endocrinology, Hospital D. Estefânia, Lisboa, Portugal.Department of Pediatric Endocrinology, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal.Department of Pediatric Endocrinology, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal.Department of Pediatric Endocrinology, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal.Department of Pediatrics, Centro Hospitalar do Tâmega e Vouga, Penafiel, Portugal.Department of Pediatric Endocrinology, Hospital de Braga, Braga, Portugal.Department of Pediatric Endocrinology, Hospital Fernando Fonseca, Lisboa, Portugal.Department of Pediatric Endocrinology, Hospital Fernando Fonseca, Lisboa, Portugal.Department of Pediatrics, Unidade Local de Saúde do Alto Minho, Viana do Castelo, Portugal.Department of Pediatrics, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.Department of Pediatrics, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.Department of Pediatric Endocrinology, Centro Hospitalar de Vila Nova Gaia e Espinho, Vila Nova de Gaia, Portugal.Department of Pediatrics, Unidade Local de Saúde do Nordeste, Bragança, Portugal.Genetics Unit, Department of Pathology, Oporto Medical School, Porto, Portugal.Department of Medical Genetics, Centro Hospitalar Universitário de S. João, Porto, Portugal.Department of Medical Genetics, Centro Hospitalar Universitário de S. João, Porto, Portugal.Department of Pediatric Endocrinology, Centro Materno-infantil do Norte, Porto, Portugal.Department of Pediatrics,<bold></bold> Centro Hospitalar Universitário de S. João, Porto, Portugal.Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.Department of Endocrinology, Instituto Português de Oncologia de Coimbra Francisco Gentil, Coimbra, Portugal.Department of Pediatrics, Hospital D. Estefânia, Lisboa, Portugal.Department of Pediatrics, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal.Department of Pediatrics, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal.Department of Pediatrics, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal.Department of Pediatric Endocrinology, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.Department of Pediatric Endocrinology, Centro Materno-infantil do Norte, Porto, Portugal.No affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study

Language

eng

PubMed ID

30889569

Citation

Santos-Silva, Rita, et al. "CYP21A2 Gene Pathogenic Variants: a Multicenter Study On Genotype-Phenotype Correlation From a Portuguese Pediatric Cohort." Hormone Research in Paediatrics, vol. 91, no. 1, 2019, pp. 33-45.
Santos-Silva R, Cardoso R, Lopes L, et al. CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort. Horm Res Paediatr. 2019;91(1):33-45.
Santos-Silva, R., Cardoso, R., Lopes, L., Fonseca, M., Espada, F., Sampaio, L., Brandão, C., Antunes, A., Bragança, G., Coelho, R., Bernardo, T., Vieira, P., Morais, R., Leite, A. L., Ribeiro, L., Carvalho, B., Grangeia, A., Oliveira, R., Oliveira, M. J., ... Borges, T. (2019). CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort. Hormone Research in Paediatrics, 91(1), 33-45. https://doi.org/10.1159/000497485
Santos-Silva R, et al. CYP21A2 Gene Pathogenic Variants: a Multicenter Study On Genotype-Phenotype Correlation From a Portuguese Pediatric Cohort. Horm Res Paediatr. 2019;91(1):33-45. PubMed PMID: 30889569.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort. AU - Santos-Silva,Rita, AU - Cardoso,Rita, AU - Lopes,Lurdes, AU - Fonseca,Marcelo, AU - Espada,Filipa, AU - Sampaio,Lurdes, AU - Brandão,Carla, AU - Antunes,Ana, AU - Bragança,Graciete, AU - Coelho,Raquel, AU - Bernardo,Teresa, AU - Vieira,Paula, AU - Morais,Rita, AU - Leite,Ana Luísa, AU - Ribeiro,Luís, AU - Carvalho,Berta, AU - Grangeia,Ana, AU - Oliveira,Renata, AU - Oliveira,Maria João, AU - Rey,Vicente, AU - Rosmaninho-Salgado,Joana, AU - Marques,Bernardo, AU - Garcia,Ana Margarida, AU - Meireles,Andreia, AU - Carvalho,Joana, AU - Sequeira,Ana, AU - Mirante,Alice, AU - Borges,Teresa, AU - ,, Y1 - 2019/03/19/ PY - 2018/11/07/received PY - 2019/02/01/accepted PY - 2019/3/20/pubmed PY - 2019/11/26/medline PY - 2019/3/20/entrez KW - CYP21A2 KW - 21 Hydroxylase deficiency KW - Congenital adrenal hyperplasia KW - Genotype–phenotype correlation SP - 33 EP - 45 JF - Hormone research in paediatrics JO - Horm Res Paediatr VL - 91 IS - 1 N2 - 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. SN - 1663-2826 UR - https://www.unboundmedicine.com/medline/citation/30889569/CYP21A2_Gene_Pathogenic_Variants:_A_Multicenter_Study_on_Genotype_Phenotype_Correlation_from_a_Portuguese_Pediatric_Cohort_ L2 - https://www.karger.com?DOI=10.1159/000497485 DB - PRIME DP - Unbound Medicine ER -