Congenital Adrenal Hyperplasia



Congenital adrenal hyperplasia (CAH) results from a deficiency in one of the enzymes involved in cortisol biosynthesis. CAH affects about 1 in 5,000 births, with a carrier frequency of 1 in 35. In about 95% of cases, CAH is caused by deficiency of the 21-hydroxylating enzyme encoded by the CYP21A2 gene.


The intended use of this P050-C1 CAH probemix is the detection of large CYP21A2 gene deletions. This product should be used in conjunction with sequence analysis. Some frequent point mutations in CYP21A2 gene can also be detected with this product but reciprocal exchanges between CYP21A2 and its pseudogene will be missed. This P050-C1 probemix is provided with a vial of SD039 reference DNA. More information on SD039 can be found in the product description.


The inactive pseudogene CYP21A1P is located at very close distance from CYP21A2. Both genes have 10 exons and are about 3.4 kb long. The great majority of the CYP21A2 mutant alleles are due to recombination between CYP21A2 and CYP21A1P. Approximately 20% of mutant alleles have DNA deletions of 30 kb that have been generated by unequal meiotic crossing-over, whereas 75% are due to gene conversion events, where an inactivating mutation is present in the CYP21A2 gene that is usually only present in the CYP21A1P pseudogene.


Other genes in this unstable chromosomal region are the closely related complement genes C4A and C4B and the TNXB gene and its pseudogene TNXA. Orientation of these genes is as displayed in Figure 1 (page 2). More information on CAH can be found in the review of White and Speiser, Endocr Rev. 21:245-291 (2000) and in NCBI GeneReviews.


The P050-C1 MLPA probemix contains 8 probes for CYP21A2 and 4 probes specific for the CYP21A1P pseudogene. Among the CYP21A2-specific probes are probes that are sensitive to the I172N, V237E (V236E), M239K (M238K), F306+T, I2G and the 8 nt deletion mutations. The mix furthermore contains 6 probes for TNXB gene and 1 for ATF6B in order to further define CYP21A2 gene deletions. Finally, 8 reference probes detecting sequences on various chromosomes are included.