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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.

journal of pediatric endocrinology and metabolism

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