21-hydroxylase deficiency in Brazil

We determined the frequency of large rearrangements and point mutations in 130 Brazilian patients with 21-hydroxylase deficiency and correlated genoty pe with phenotype, The frequency of CYP21 deletions was lower (4.3%) than i n most of the previous series described, whereas the frequency of large gen e conversions was similar to the frequency reported in the literature (6.6% ). The most frequent point mutations were 12 splice (41.8% in salt wasting - SW), I172N (32.6% in simple virilizing - SV) and V281L (40.2% in the late onset form - LO). The frequency of the nine most common point mutations wa s similar to that reported for other countries. The 93 fully genotyped pati ents were classified into 3 mutation groups based on the degree of enzymati c activity (A<2%, B <congruent to> 2%, C>20%). In group A, 62% of cases pre sented the SW form; in group B, 96% the SV form, and in group C, 88% the LO form. We diagnosed 80% of the affected alleles after screening for large r earrangements and 15 point mutations. To diagnose these remaining alleles w e sequenced the CYP21 gene of one patient with the SV form and identified a heterozygous G-->A transition in codon 424. This mutation leads to a subst itution of glycine by serine in a conserved region and was also found in a compound heterozygous state in 4 other patients. The mutation G424S present ed a linkage disequilibrium with CYP21P and C4A gene deletions and HLA DR17 , suggesting a probable founder effect. Search for the G424S mutation in ot her populations will reveal if it is restricted to the Brazilian patients o r if it has a wider ethnic distribution.