Because of the complexity of the genetic structure of the CYP21A2 locus, and the possibility that a patient’s congenital adrenal hyperplasia (CAH) may be due to other gene defects, genetic testing results should be correlated carefully with clinical and biochemical data.
This testing strategy is superior to approaches previously used, but may still miss some complex and large-scale genetic rearrangements or deletions, as well s genetic changes in far upstream or downstream gene-regulatory elements that impair CYP21A2 gene expression. This can lead to false-negative test results.
Rare polymorphisms in primer binding sites can lead to selective allelic drop-out, which can lead to false-negative or false-positive diagnosis.
Patients without genetic evidence for disease-causing CYP21A2 genetic changes may still suffer from CAH, but due to a different enzyme defect. Additional and expanded biochemical steroid profiling is, therefore, recommended if the clinical picture is strongly suggestive of CAH.