Molecular genetic analysis in 93 patients and 193 family members with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia

• Published in: The Journal of steroid biochemistry and molecular biology 2017-01, Vol.165 (Pt A), p.51-56
• Main Authors: Dumic, Katja K., Grubic, Zorana, Yuen, Tony, Wilson, Robert C., Kusec, Vesna, Barisic, Ingeborg, Stingl, Katarina, Sansovic, Ivona, Skrabic, Veselin, Dumic, Miroslav, New, Maria I.
• Format: Article
• Language: English
• Subjects: 21-Hydroxylase deficiency; Adrenal Hyperplasia, Congenital - ethnology; Adrenal Hyperplasia, Congenital - genetics; Alleles; Child; Child, Preschool; Cohort Studies; Croatia; CYP21A2 gene; Female; Genetic analysis; Genetic Association Studies; Genetic counseling; Genetic variability; Genotype; Genotype & phenotype; Genotypes; Genotyping; HLA Antigens - chemistry; Humans; Hydroxylase; Hyperplasia; Infant; Infant, Newborn; Male; Mutation; Patients; Pedigree; Phenotype; Point Mutation; Prenatal diagnosis; Siblings; Steroid 21-Hydroxylase - genetics; Studies
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2016.03.035

•Genotype-phenotype correlation in patients with congenital adrenal hyperplasia due to 21-hydroxylased deficiency (21-OHD CAH) is variable.•Genotype-phenotype discordance is observed in HLA identical siblings with 21-OHD CAH.•Genotyping of family members of 21-OHD CAH patients is important in order to avoid pitfalls in genetic counseling.•High frequency of the p.R357W mutation of CYP21A2 gene is found among Croatian 21-OHD CAH patients. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency is caused by mutation in the CYP21A2 gene. The frequency and spectrum of CYP21A2 mutations and genotype-phenotype correlations among different populations are variable. Aim of this study was to define mutation frequency and spectrum of CYP21A2 gene mutations in patients with classical 21-hydroxylase deficiency (21OHD) and their family members in Croatia and study genotype-phenotype correlation. Clinical features and mutations of CYP21A2 gene in 93 unrelated 21OHD patients and 193 family members were examined. In this cohort, 66 patients were affected with salt wasting (SW) form, and 27 were affected with simple virilizing (SV) form of the disease. Mutations were identified in both alleles (67% compound heterozygous and 33% homozygous) in 91 of 93 patients. Deletions and conversions were found in 18.8% and point mutations in 79.6% alleles. Mutations in 3 alleles (1.6%) remained unidentified (in one patient we found only one, while in other no mutations were found at all). The most common point mutations were Intron 2 splice mutation IVS2-13 A/C>G (35.5%) and p.R357W (16.7%). Genotypes were categorized into Groups 0, A, B and C according to the extent of enzyme impairment. Genotype-phenotype concordance was 100%, 85% and 75% for Groups 0, A and B, respectively. Since only classical 21OHD patients were studied, Group C comprised solely p.P31L mutation and had 73% patients with SV and 27% with SW phenotype. Intrafamilial phenotypic variability was found in two families. CYP21A2 genetic analysis in 193 family members showed that 126 parents were heterozygous carriers, 3 were newly discovered patients, 2 fathers were not biological parents, and mutations were not detected in 3. Among 59 siblings, 32 were heterozygous carriers, 15 carried normal alleles, and 12 were patients (4 newly diagnosed). Genotype-phenotype divergence observed in this study suggests caution in preconceptional counseling and prenatal diagnosis of CAH. High frequency of p.R357W mutation was fou