21-Hydroxylase Genotyping in Australasian Patients with Congenital Adrenal Hyperplasia

Abstract

Mutations in CYP21 (21-hydroxylase) lead to congenital adrenal hyperplasia (CAH). We genotyped 26 probands with CAH by PCRsequencing the entire CYP21 gene. 25/26 had homozygous or compound heterozygous mutations. The frequencies of mutations were similar to other populations with deletion/hybrid, 12 G splice and I172N the most common. Five patients with a 1172N allele predicting simplevirilising CAH had a salt-wasting phenotype. Two other probands also had a more severe phenotype than predicted by genotype. Two families had both non-classic and salt-wasting phenofypes arising from combinations of three deleterious alleles. Two novel CYP21 alleles were detected: D106N and a large deletion encompassing CYP21 and adjacent pseudogene. Two rare CYP21 alleles were also found. Three of these four novel/rare alleles were only detected as a result of sequencing the entire CYP21 gene. Entire CYP21 sequencing will increase the number of mutations detected in CAH, and in combination with functional studies should contribute a greater understanding of phenotype-gcnotype correlations. KEY WORDScongenital adrenal hyperplasia, 21-hydroxylase deficiency, genotyping

Novel variants of CYP21A2 in Vietnamese patients with congenital adrenal hyperplasia

“…The proportion of I2G and p.I172N variants vary significantly between populations. Compared to other Asian populations, I2G and p.I172N variants in our cohort was similar with the Japanese (26.5% and 11.8%) and Australian (34.4% and 11.3%) cohorts but was lower than Chinese population (41.5% and 22.3%) (Asanuma et al., ; Jeske et al., ; Lee et al., ). p.V281L variant is most common in North and South America populations (Marino et al., ; New et al., ), but in our cohort, the prevalence was low (0.74%).…”

“…, Denmark: 36.8% (Ohlsson, Müller, Skakkebaek, & Schwartz, 1999), Middle Europe: 30.6% (Dolzan et al, 2005), Czech: 38.6% (Vrzalová et al, 2011), and Australia: 33.5% (Jeske et al, 2009). p.R356W variant in Vietnam was higher than most European populations (0%-9.8%) but was similar with Chinese and Japanese populations (15.4% and 17.6%, respectively) (Asanuma et al, 1999;Lee et al, 1998).…”

Ethnic and gender differences in rates of congenital adrenal hyperplasia in Western Australia over a 21 year period

“…21-hydroxylase deficiency (21-OHD) accounts for more than 90% of all CAH cases 1 and is caused by mutations in the CYP21 gene located on the short arm of chromosome 6. 6 Early diagnosis and treatment is necessary to prevent adrenal crisis and early infant death in the classical-congenital adrenal hyperplasia (C-CAH) of the SW form of 21-OH deficiency. [2][3][4] Complete enzyme deficiency with combined impairment of cortisol and aldosterone synthesis results in the early onset classical CAH (C-CAH), the salt-wasting (SW) form.…”

Sequence Analysis of CYP21A1P in a German Population to Aid in the Molecular Biological Diagnosis of Congenital Adrenal Hyperplasia

“…Investigators have developed a large number of methods that can detect mutations and singlenucleotide polymorphisms in CYP21A2, such as the amplification-created restriction site approach (7 ), multiplex minisequencing (8 ), and direct gene sequencing (9,10 ). In addition, functional and expression studies have been used in in vitro assays to search for novel mutations (11)(12)(13)(14).…”