Genotype-Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency Using...

Although there a well-known correlation in genotype and phenotype, patients with 21-OHD caused by severe pathogenic variants have better correlation, whereas inconsistencies are more common in the presence of milder variants. This study aimed to evaluate CYP21A2 genotyping and reveal the genotype-phenotype correlation in children diagnosed with 21-OHD in the South-eastern Anatolia region, where ethnic diversity and consanguineous marriage rates are high.

The patients were divided into three groups: salt wasting (SW), simple virilizing (SV) and non-classical (NC). Pathogenic variants of the CYP21A2 gene were classified into six groups based on predicted 21-hydroxylase activity: null-A-B-C-D-E. CYP21A2 genotyping was performed by sequence-specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes.

The overall genotype-phenotype concordance was found to be 73.1% (68/93). The expected concordance with the SW form of the null (n = 12) and A (n = 51) groups is 91.6% and 88.2%, respectively. While the percentage of the expected clinical form of SV in patients in group B (n = 5) was 80%, the concordance for the expected clinical form of NC for group C (n = 25) was not strong enough (32%).

This study demonstrates that children with 21-hydroxylase deficiency show a good correlation between severe pathogenic variants and predicted clinical phenotypes; however, the correlation is not strong enough between milder variants. The discrepancies could have resulted from the complex characteristics of 21-OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods.