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Molecular Diagnosis of CYP21 Mutations in Congenital Adrenal Hyperplasia

Implications for Genetic Counseling

  • Molecular Diagnostic
  • Published:
American Journal of Pharmacogenomics

Abstract

Congenital adrenal hyperplasia (CAH) is an inherited disorder of steroid biosynthesis most often attributable to mutations in CYP21 (also termed CYP21A2) encoding the active steroid 21-hydroxylase enzyme. This review focuses on clinical and genetic aspects of CAH, and updates the reader on current methodology and applications for molecular genetic diagnosis.

Genotyping patients with CAH has revealed >50 mutations within CYP21, yet only 10 mutations account for ~95% of affected alleles. Many CYP21 mutations are gene conversions arising via transfer of gene sequences between the non-functional CYP21 pseudogene and CYP21.

Phenotype is generally well-correlated with genotype. Historically, CAH has been divided into 3 types of disease: classic salt-wasting, classic simple virilizing (non-salt-wasting), and nonclassic. Recent findings support the notion that rather than discrete phenotypic categories, CAH is better represented as a continuum of phenotypes, from severe to mild.

Molecular genetic diagnosis is most effectively employed now in prenatal diagnosis of classic CAH. As newborn screening for CAH becomes more widespread, genotyping may be implemented to resolve diagnostic difficulties encountered with hormonal testing. As automated methods of DNA diagnosis such as microarrays or gene chips are refined, it is likely that genetic screening will become less expensive and more readily available. The clinician should be aware of the potential for both false negatives and false positives with PCR-based gene screening. In short, whereas molecular genetic diagnosis is a valuable tool, it cannot replace clinical acumen and hormonal assays.

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  1. Division of Pediatric Endocrinology, North Shore-Long Island Jewish Health System, Department of Clinical Pediatrics, New York University School of Medicine, New York, USA

    Phyllis W. Speiser

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Speiser, P.W. Molecular Diagnosis of CYP21 Mutations in Congenital Adrenal Hyperplasia. Am J Pharmacogenomics 1, 101–110 (2001). https://doi.org/10.2165/00129785-200101020-00003

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