Genotype-Phenotype Correlation Study and Mutational Analysis in a Chinese Cohort with 21-Hydroxylase Deficiency

Abstract

Background: Steroid 21-hydroxylase deficiency (21OHD) is the most common enzymatic defect. Genotype-phenotype associations were concluded in different ethnic group. However, such correlations have not been well established in Chinese. This study aimed to analyze this correlation in a Chinese 21OHD cohort and the function of four novel mutations of CYP21A2 gene. Methods: A Chinese 21OHD cohort was enrolled to investigate the clinical, biochemical, and genetic characteristics of this disorder. Symptoms and laboratory findings of all the members were collected. Mutation analysis of CYP21A2 gene, 21-hydroxylase activity assays and in silico predictions of protein structure were performed. Genotype and phenotype associations were analyzed in both the cohort and 487 Chinese CAH patients ever reported. Findings: Among the total cohort, 47 patients (65.3%) were diagnosed as SW phenotype, 11 (15.3%) were SV type and 14 (19.4%) were NC type. Interestingly, the value of FSH and LH for the prediction of the severe SW phenotype was up to 0.862 and 0.669, respectively. Overall, the detection rate of CYP21A2 mutation was 97.9%, which revealed 25 mutations and 36 genotypes. Four novel mutations (p.L199X, p.E321del, p.H393Q and p.L459-P464del) were detected. All these four mutations were predicted to destroy 21-hydroxylase three-dimensional structure and induced a significantly reduced CYP21 activity of less than 5% compared with the wild type. Interpretation: A high consistency of genotype-phenotype association was found in SW CAH and a less matched correlation in SV and NC CAH. Moreover, FSH and LH levels were proved to be a promising marker for predicting the severity of the disease. Funding: This work was supported by grants from the National Natural Science Foundation (No. 81370891 and No. 81670720), Special Funds for Taishan Scholar Project (No. tsqn20161071). Declaration of Interests: The author reports no conflicts of interest in this work. Ethical Approval Statement: This study was approved by the Ethics Committee of the Shandong Provincial Hospital. Written informed consent was obtained from all patients or their guardians.