Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction.
Eur J Endocrinol
; 175(2): 107-16, 2016 Aug.
Article
in En
| MEDLINE
| ID: mdl-27185867
ABSTRACT
BACKGROUND:
Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations.OBJECTIVE:
To review causal mutations and genotype-phenotype correlation in 480 Brazilian patients.METHODS:
DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A <2%; B 3-7%; C >20% of residual enzymatic activity (EA); D unknown EA; E incomplete genotype).RESULTS:
Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3ng/mL was the best cutoff to identify NC-patients carrying severe mutations.CONCLUSIONS:
We identified a good genotype-phenotype correlation in CAH, providing useful data regarding prediction of disease's severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Steroid 21-Hydroxylase
/
Point Mutation
/
Adrenal Hyperplasia, Congenital
/
Genotype
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limits:
Adolescent
/
Child
/
Child, preschool
/
Female
/
Humans
/
Infant
/
Male
/
Newborn
Country/Region as subject:
America do sul
/
Brasil
Language:
En
Journal:
Eur J Endocrinol
Journal subject:
ENDOCRINOLOGIA
Year:
2016
Document type:
Article