The distribution of intrafamilial CYP21A2 mutant alleles and investigation of clinical features in Turkish children and their siblings in Southeastern Anatolia.

Background The genotype-phenotype relationship shows regional variability in 21-hydroxylase deficiency (21-OHD) caused by mutations in the CYP21A2 gene. This study focuses on the genotype-phenotype compatibility between patients and their siblings in a region where consanguineous marriage is common. Methods The most common mutations (I2G-P30L-I172N-V237E-M239K-V281L-Q318X-R356W-F306 + nt) were studied in 60 children with 21-OHD and 40 siblings (12 symptomatic and 28 asymptomatic; mean age 5.89 ± 4.63 and 8.34 ± 2.22 years, respectively). The allele number (patients; 93 siblings; 70 alleles) was counted for each case. Salt wasting (SW; n = 38), simple virilizing (SV; n = 11) and non-classical congenital adrenal hyperplasia (NCCAH; n = 11) types were compared with their genotypes classified into groups Null-AB-C-D-E based on enzyme impairment. Results Disease-causing mutations were identified in unrelated alleles: 80 out of 93 alleles (86%) in the patients: SW, 51/56 (91%); SV, 14/16 (87.4%) and NCCAH, 15/21 (71.4%). There were 43 out of 70 alleles (61.4%) in the siblings (asymptomatic, 25/50 [50%]; symptomatic, 18/20 [90%]). The most frequently detected mutations in the patients were: I2G (22%), Q318X-P30L-V281L (13% each). The distribution of the most common mutations by clinical types was: SW: I2G-Q318X (30.2%-19.6%), SV: I172NI2G (37.5%-18.7%), NCCAH: V281L-P30L (33.3%-28.5%). In patients and symptomatic siblings, the concordance percentages by genotype groups were: Null (100%-100%), A (85%-60%), B (100%-Not applicable), C (41.6%-50%). Eleven out of 28 asymptomatic siblings had disease-causing mutations (four, severe; one, moderate; six, mild). The distribution of genotypes by phenotypes were: SW: Null-A (88%), SV: B-A (50%-41.6%), NCCAH: C (100%). Conclusions This study showed that the most common alleles were IN2G-Q381X-R356W-P30L-V281L in the children with 21-OHD and asymptomatic siblings, and that the phenotype can be predicted from the genotype except for the P30L-V281L. This result suggests that the most common mutations in 21-OHD are similar to previous reports, but that the genotype-phenotype compatibility is good except for group C showing regional variability, and that genotyping of siblings discovered new patients.