Identification of novel and rare CYP21A2 variants in Chinese patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia due to CYP21A2 gene mutation. The aim of study is to expand CYP21A2 mutational spectrum in the Chinese population and to provide novel genetic information in terms of ethnic diversity.95 Chinese suspected 21-OHD patients with phenotypes varying from salt-wasting (SW) to nonclassic symptoms were recruited. The clinical characteristics were retrospectively analyzed. Sanger sequencing and multiplex ligation-dependent probe amplification were used to detect point mutations and large gene deletions, respectively.20 different mutant alleles were detected in 35 patients with 21-OHD. The most common variant was c.293-13A/C>G (30.0%), followed by p.I173N (20.0%), large gene conversions (14.3%), large gene deletions (11.4%), and p.R484Pfs*58 (4.3%). Remarkably, we identified a novel F450L variant, in silico predicted to be associated with the salt-wasting form. Two variants including p.R409C and p.R427H, previously considered as conserved in specific ethnicities due to a founder effect, were detected in our cohort. Further, a rare p.H63L + p.V70L variant, hitherto only observed in the Chinese population, in trans with different variants corresponding to the salt-wasting form resulted in diverse phenotypes.One novel and four rare variants of CYP21A2 gene corresponding to severe phenotypes were identified in our cohort. Two variants including p.R409C and p.R427H have wider ethnic distributions. Therefore, the sequence of CYP21A2 gene must be analyzed carefully in case rare or novel deleterious variants exist. Our findings improve the understanding of CYP21A2 mutational spectrum in 21-OHD patients and contribute to the precise diagnosis and prenatal counseling.