Mutational spectrum of steroid 21-hydroxylase (21-OH) gene. Genotype-phenotype correlation in 360 Argentinian congenital adrenal hyperplasia (CAH) patients.

MARINO ROXANA M,; PEPE CAROLINA M,; RAMIREZ PABLO C,; GALEANO JESICA,; PEREZ GARRIDO NATALIA I,; CHALER EDUARDO,; MACEIRAS MERCEDES,; CIACCIO MARTA,; WARMAN MONICA,; DUJOVNE NOELIA,; GENIUK NADIA,; GRYNGARTEN MIRTA,; BERGADÁ IGNACIO,; ESCOBAR MARIA E,; BALBI VIVIANA,; RIVAROLA MARCO A,; BELGOROSKY ALICIA,

New York, USA

Congreso; LWPES/ESPE 8th Joint Meeting; 2009

Body: Deficiency of 21-OH is the most common form of CAH.We determined the frequency of 11 most common mutations described in the CYP21A2 gene by allele-specific PCR and southern blot analysis.In non-detected alleles coding and exon-intron boundaries sequence was carried out by automated sequencing.The correlation between genotype and phenotype in 360 patients (690 unrelated chromosomes)with the classical (CF,192)and non-classical (NCF,168) forms of CAH-21OH was also analyzed.In2 (36%) in salt wasting (SW), I172N (37.5%) in simple virilizing (SV) of the CF, and V281L (54.7%) in the NCF were the most prevalent mutations.The frequencies found were V281L 25.5%,In2 20.86%,I172N 8.98%,Q318X 7.24%,R356W 3.76%,ClEx6 2.31%,R483fs 1.44%,Ex3 1.01%,P453S 1.01%,P30L 0.57%.Large rearrangement (DEL/CONV)frequency was lower than in most populations but similar to brazilian and mexican populations (10.86%).The screening of 11 most common mutations allowed for the detection of 88.1% of affected alleles (80.94% for the NCF and 94.4% for the CF).The 295 patients with both detected alleles were classified into 5 different genotype groups according to the predicted severity of the mutations as previously described by Wedell et al. JCEM,1994(null:0%; A:In2; B:I172N; C:>20%; D:20%, chimeric gene promCYP21P+P30L; as the allele determining phenotype).In group null 100% of cases presented SW form, in group A 82.7% the SW form, in group B 83.3% the SV form and in group C 99.2% the NCF.In group D (n=4) one female patient presented an early manifestation of NCF while in the other 3 patients a CF(SV) was diagnosed.Sequence analysis revealed the presence of 8 rare mutations previously described and in 2 patients a novel nonsense mutation Y49X was found (In2/Q41X, Q318X/Q41X).The presence of a premature stop codon would predict a truncated protein without enzymatic activity that correlates with the SW phenotype found in both patients.The high correlation between genotype and phenotype found in CAH-21OH patients confirms the usefulness of molecular studies to predict the clinical outcome and its application in genetic counseling.The analysis of 11 most common mutations in our population allowed to detect a high percentage of CYP21A2 affected alleles.The different detection level of the affected alleles between CF and NCF would suggest that heterocygote carriers could have been included in the NC group of patients, and it confirms the overestimation of the NC form by hormonal laboratory studies.