Many patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency have CAH-X syndrome, a connective tissue dysplasia consistent with hypermobility-type Ehlers-Danlos syndrome due to a contiguous gene deletion involving the adjacent CYP21A2 and TNXB genes.
Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity.
A total of 1143 obligate carriers of a CYP21A2 mutation (561 men) were identified from the Swedish National CAH Registry, encompassing >700 patients and the Multi-Generation Registry to identify their parents.
We have designed an efficient multistep approach to diagnose and classify CAH cases due to CYP21A2 variant and to study the genotype-phenotype relationship.
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is autosomal recessive disorder of cortisol biosynthesis.Genetic defects in CYP21A2 cause 21OHD.
The simple virilizing (SV) form of congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder usually caused by steroid 21-hydroxylase deficiency due to I172N missense mutation at the CYP21A2 gene.
More than 95% of congenital adrenal hyperplasia (CAH) cases are associated with mutations in the 21-hydroxylase gene (CYP21A2) in the human leukocyte antigen (HLA) class III area on the short arm of chromosome 6p21.3.
The aim of this study was to re-visit the association between the CYP21A2 variants and HLA polymorphisms in a large ethnically diverse cohort of patients with CAH who underwent comprehensive CYP21A2 genotyping, including specification of chimeric gene subtypes (CAH CH-1 through CH-9 of CYP21A1P/CYP21A2 chimeras; CAH-X CH-1 through CH-3 of TNXA/TNXB chimeras) in alleles with 30-kb deletions.
Methods Children with increased serum 17-OHP levels, and without disease-related clinical features during follow-up, underwent the entire CYP21A2 gene sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis (SALSA MLPA P050B CAH).
Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH.
Total DNA isolated from the peripheral blood of the two probands was screened for potential mutations in the following susceptibility genes of CAH: CYP21A2, CYP11B1, CYP17A1, HSD17B3, HSD3B2, ARMC5, and STAR using Target Capture-Based Deep Sequencing; and Sanger sequencing was conducted for the family members to detect the potential mutations.
Classical 21-hydroxylase deficiency (21-OHD) due to mutations in the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene is the most common type of congenital adrenal hyperplasia (CAH).
The second CYP21A2 was free ofCAH-causing mutations and produced mRNA in the adrenal gland, confirming its functionality and ability to rescue the carriers from CAH.