CYP21A2 Gene Mutations in Congenital Adrenal Hyperplasia: Genotype-phenotype correlation in Turkish children

Abstract

Background: Congenital adrenal hyperplasia (CAH) due 21−hydroxylase deficiency (21−OHD) is a common autosomal recessive disorder. It is caused by defects in the CYP21A2 gene.Objective: Our aim was to determine the frequency of common gene mutations and to evaluate genotype−phenotype correlations in Turkish 21−OHD patients.Methods: Molecular analysis of the CYP21A2 gene was performed for the detection of the eight most common point mutations [p.P30L, IVS2−13C>G (IVS−2), p.I172N, exon 6 mutation cluster (p.I236N, p.V237E, p.M239K), p.V281L, p.Q318X, p.R356W, 8−bp−deletion], of large deletion and conversion by southern blotting, allele specific semi−quantitative PCR/enzyme restriction method and sequencing, in 56 patients with 21−OHD, from 52 families.Results: Disease−causing mutations were identified in 77 out of 91 alleles (84.6%) of the patients. Mutations were found in 34 of 43 alleles (79.1%) in salt wasting (SW; n=26), 32 of 36 alleles (88.8%) in simple virilizing (SV; n=24) and 11 of 12 alleles (91.6%) in non−classical (NC; n=6) form of CAH. The most frequent mutations were IVS−2 (22.0%), large conversion (14.3%), p.I172N (9.9%) p.R356W (8.8%), and large deletion (6.6%). In the SW form, the most frequent genotypes were homozygous for IVS−2 (11.5%) and homozygous for large conversion of the gene (11.5%). In the SV form, the most frequent genotype was homozygous for IVS−2 (20%), followed by compound heterozygous for p.I172N/8−bp del (10%). Homozygous for p.V281L (16.7%) was most common in NC. In most cases there was good correlation between genotype and phenotype. In the SW and NC forms, genotypes of all the patients correlated with their phenotypes. Conclusions: This is the first comprehensive study on the molecular basis of CAH patients in the Turkish population. Based on these results, we propose a modified screening strategy to facilitate molecular testing of CAH patients in our population.Conflict of interest:None declared.

Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations

“…In Serbia, CYP21A1P/CYP21A2 chimeras accounted for 13 % of all unrelated alleles which is a lower frequency than reported for other European countries (Slovenia 48.5 %; Hungary 24.5 %; Turkey 20.9 %; Romania 16.7 %; Greece 13.5 %) [11,[24][25][26][27]. Interestingly, p.R356W mutation with 11.1 %, appears particularly frequent in Serbian population when referenced to other reports (Slovenia 0 %, Greece 0.45 %, Romania 1.5 %, Macedonia 4.2 % and Hungary 3 %) [11,[23][24][25]27], whereas a comparable frequency of this mutation was reported in Turkish (8.8 %) [26] and Croatian (14 %) [20] populations. Similarly, frequency of p.G110fs was found to be higher (7.4 %) in comparison to surrounding populations (Slovenian 0 %, Croatian 3 %, Romanian 0 %) [11,20,25] as well as to other European countries (Greece 2.25 %; France 3 %; Turkey 4.4 %) [26][27][28].…”

“…As documented for many other populations, the most prevalent mutation in Serbia was c.290-13A/C>G, accounting for 18.5 % of alleles. However, this frequency was lower comparing to majority of neighboring countries (Croatia 32 %; Hungary 35.9 %; Romania 43.9 %; Macedonia 60.4 %) [22][23][24][25], but it was similar to those of Slovenian (16.7 %) [11] and Turkish populations (22 %) [26]. Second most frequent point mutation was p.P30L missense mutation with relative frequency of 13 %, similar to those in Greece 11.3 % [27] and Austria 9.2 % [24].…”

“…Second most frequent point mutation was p.P30L missense mutation with relative frequency of 13 %, similar to those in Greece 11.3 % [27] and Austria 9.2 % [24]. In many other European countries (Slovenia, France, Italy, Hungary, Czech Republic and Spain) this mutation is found on less than 5 % of alleles, while in Table 3 Genotype and phenotype of patients with CAH from Serbia a This group includes CH-Ex3 chimera characterized with variable residual enzyme activity, novel mutations not yet studied in vitro and heterozygotes Turkey it was not found at all [24][25][26][28][29][30]. In Serbia, CYP21A1P/CYP21A2 chimeras accounted for 13 % of all unrelated alleles which is a lower frequency than reported for other European countries (Slovenia 48.5 %; Hungary 24.5 %; Turkey 20.9 %; Romania 16.7 %; Greece 13.5 %) [11,[24][25][26][27].…”

“…In many other European countries (Slovenia, France, Italy, Hungary, Czech Republic and Spain) this mutation is found on less than 5 % of alleles, while in Table 3 Genotype and phenotype of patients with CAH from Serbia a This group includes CH-Ex3 chimera characterized with variable residual enzyme activity, novel mutations not yet studied in vitro and heterozygotes Turkey it was not found at all [24][25][26][28][29][30]. In Serbia, CYP21A1P/CYP21A2 chimeras accounted for 13 % of all unrelated alleles which is a lower frequency than reported for other European countries (Slovenia 48.5 %; Hungary 24.5 %; Turkey 20.9 %; Romania 16.7 %; Greece 13.5 %) [11,[24][25][26][27]. Interestingly, p.R356W mutation with 11.1 %, appears particularly frequent in Serbian population when referenced to other reports (Slovenia 0 %, Greece 0.45 %, Romania 1.5 %, Macedonia 4.2 % and Hungary 3 %) [11,[23][24][25]27], whereas a comparable frequency of this mutation was reported in Turkish (8.8 %) [26] and Croatian (14 %) [20] populations.…”

Expanded genetic screening panel for the Ashkenazi Jewish population

“…26 In addition, the common mutations for congenital adrenal hyperplasia were added; p.P30L, IVS2 13C>G (IVS 2), p.I172N, exon 6 mutation cluster (p.I236N, p.V237E, p.M239K), p.V281L, p.Q318X, p.R356W, and an 8 bp deletion in exon 3. 27 …”