Genotype-Phenotype Correlation in CAH Patients with Severe CYP21A2 Point Mutations in the Republic of Macedonia

Abstract

Steroid 21-hydroxylase deficiency is a most frequent cause of congenital adrenal hyperplasia (CAH), due to mutations in the CYP21A2 gene. Approximately 75% of patients with classical form of CAH have severe impairment of 21-hydroxylase activity. Methods: We have performed direct molecular diagnosis of the nine common CYP21A2 point mutations in 24 Macedonian CAH patients from 20 unrelated families, using differential PCR and ACRS. Results: Five of the analysed mutations were detected in 23 patients: 15 patients were homozygous for one mutation, four patients were compound heterozygotes and four patients were heterozygotes. The most common was IVS2-13A/C mutation found in 60.4% of the alleles, followed by Q318X (22.9%), R356W (4.2%), V281L (2.1%) and P30L (2.1%). The concordance of genotype to phenotype in the patients was 83.3% with complete concordance in the genotypes predicting the SW and SV phenotype. Conclusion: The distribution of the detected mutations in the Macedonian CAH patients was similar with those described in other European populations. The genotype-phenotype correlation observed in our patients strengthens the fact that the genotype cannot be completely predictive of phenotype.

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].…”

“…To the best of our knowledge, allele carrying two known mutations, p.P30L and p.P453S (c.[86C>T; 1357C>T]) has not been previously described. It should be noted that only the most frequent mutations were analyzed in majority of studies reporting molecular genetic base of various European populations [22,23]. Therefore, the lack of alleles with multiple mutations in the literature might be a consequence of low-resolution genotyping characteristic for the older studies [24].…”

21-Hydroxylase Deficiency Associated with Male Infertility: Report of 2 Cases with Gene Analyses

“…Mutational analysis for the 21-hydroxylase gene from affected patients has demonstrated an association between enzymatic impairment and clinical manifestations (9), and genotype-phenotype relationships have been documented (10). In the present cases, genetic analysis of the CYP21A2 gene revealed mutations of I172N (Ile to Asn) in exon 4 and R356W (Arg to Trp) in exon 8 in Case 1, as well as I172N (Ile to Asn) in exon 4 in Case 2.…”

Identification of a novel compound heterozygous mutation of the CYP21A2 gene causing 21‑hydroxylase deficiency in a Chinese pedigree

“…Baumgartner-Parzer et al ( 25 ) reported that the consistency between genotype and clinical phenotype was 80%. However, genotype and clinical phenotype are not always completely consistent, and the same 21-OHD gene mutation in patients with CAH may result in different clinical phenotypes ( 26 , 27 ). New et al ( 28 ) reported that certain mutations, including the P30L, I2Gand I172N mutations, were prone to yield different CAH phenotypes.…”