CYP11B1 gene mutations in patients congenital adrenal hyperplasia in Turkey

Abstract

Background: Congenital adrenal hyperplasia (CAH) due to11b-hydroxylase deficiency (11OHD), a rare autosomal recessivedisorder, is the second most common form of CAH, resulting inglucocorticoid deficiency, hyperandrogenism and hypertension.Objective and hypotheses: To investigate the specific CAHmutations in CYP11B1 gene and to examine for genotypephenotypecorrelations. Method: 21 patients (nZ9, 46, XX;nZ12, 46, XY) with the classical 11OHD from 20 unrelatedTurkish families were included in this study. Diagnosis of 11OHDwas based on both clinical and hormonal criteria. Mutationscreening of CYP11B1 gene was performed using direct Sangersequencing analysis. Known mutations were confirmed bydatabase and literature search. Novel mutations were analyzedby in silico prediction tools (PolyPhen-2, SIFT and MutationTaster). Results: The age of diagnosis at onset ranged from 6 daysto 12.5 years. The rate of consanguinity was very high (75%). Fourout of nine 46, XX patients received a late diagnosis (age 2–8.7years) and were raised as males due to severe masculinization(Prader genital stages IV and V). Mutation analyses in 20 indexpatients revealed 12 different mutations in CYP11B1 gene. Thesemutations were homozygous (HM) p.L299P (30%, 6/20), HMp.R141X (10%, 2/20), HM c.954GOA (silence, cryptic splicing;10%, 2/20), HM IVS8C2TOC (novel splice-donor mutation, 5%,1/20), compound heterozygous (CHT)((p.L299P)C(IVS8C2TOC); 5%, 1/20), HM p.W116C (5%, 1/20), HM p.R384Q (5%, 1/20),HM p.R448C (5%, 1/20), HM c.1449_1451delGGT (5%, 1/20),CHT ((G393CAG)C(p.L299P)); 5%, 1/20), HMc.1179_1180dupGA (novel; 5%, 1/20) and HM p.R143P (novelmissense; 5%, 1/20). One patient had mutation in only one allele(p.T318M). There was no definitive correlation between genotypeand phenotype. Conclusion: In this study, three different novelmutations were detected and the p.L299P was found to be the mostcommon mutation. The results of the study might contribute tothe establishment of molecular screening strategies. Identificationof the disease causing mutations provides reliable information forgenetic counseling for the families.