CYP21A2 gene pathogenic variants: a multicenter study on genotype-phenotype correlation from a Portuguese Pediatric Cohort

Rita Santos-Silva, Rita Cardoso, Lurdes Lopes, Marcelo Fonseca, Filipa Espada, Lurdes Sampaio, Carla Brandão, Ana Antunes, Graciete Bragança, Raquel Coelho, Teresa Bernardo, Paula Vieira, Rita Morais, Ana Luísa Leite, Luís Ribeiro, Berta Carvalho, Ana Grangeia, Renata Oliveira, Maria João Oliveira, Vicente ReyJoana Rosmaninho-Salgado, Bernardo Marques, Ana Margarida Garcia, Andreia Meireles, Joana Carvalho, Ana Sequeira, Alice Mirante, Teresa Borges

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12 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)33-45
Number of pages13
JournalHormone Research in Paediatrics
Issue number1
Publication statusPublished - 1 May 2019
Externally publishedYes


  • 21 Hydroxylase deficiency
  • Congenital adrenal hyperplasia
  • CYP21A2
  • Genotype-phenotype correlation


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