title: 21-hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype-phenotype correlation and identification of nine novel mutations.
abstract: Steroid 21-hydroxylase deficiency (21-OHD) caused by the CYP21A2 gene mutations accounts for more than 90% of congenital adrenal hyperplasia (CAH) cases. In this study, molecular defects of 230 patients with 21-OHD were investigated. Point mutations of CYP21A2 gene were analyzed by Sanger sequencing, and large gene deletions were detected by multiplex ligation-dependent probe amplification (MLPA). Nine micro-conversions and 18 spontaneous mutations accounted for 74.6% of alleles, while large gene deletions and large gene conversions accounted for 25.4% of alleles. The most frequent micro-conversion was c.292-13A/C>G (I2G) (35%), followed by p.I173N (14.3%), p.R357W (5.9%) and p.Q319* (4.6%). Nine novel mutations were identified in these patients, which were predicted to hamper the 21-hydroxylase protein function in varying degrees. Genotype and phenotype correlated well in 89.6% of our patients, but disparity in phenotypic appearance also appeared in a small portion of the patients. 16.1% of the patients carried homozygous genotypes while 83.9% of patients carried compound heterozygous mutations. We concluded that the frequency of CYP21A2 mutations in our study was slightly different from those reported for other ethnic groups. Micro-conversions were the main category of the mutation spectrum, while large deletions and large gene conversions could also cause 21-OHD. A large portion of different types of the compound heterozygous genotypes may partially contribute to the discordance in genotype-phenotype comparison. This study expanded the CYP21A2 mutation spectrum of Chinese patients and could be helpful in prenatal diagnosis and genetic counseling for 21-OHD patients.
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Yongguo
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Lianshu
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Zhuwen
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China. Electronic address: gu_xuefan@163.com.
authors.forename: Xuefan
authors.initials: X
authors.lastname: Gu
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010641:Phenotype; D017354:Point Mutation; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
chemical_list: C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase
keywords: 21-Hydroxylase deficiency; CYP21A2 gene; Congenital adrenal hyperplasia; Genotype–phenotype correlation; Mutational spectrum