ClinVar

Most mutations in the CYP21 gene causing congenital adrenal hyperplasia (201910) are deletions. Amor et al. (1988) reported the cloning and characterization of a nondeleted mutant CYP21B gene. Codon 172 of the mutant gene was found to be changed from ATC, encoding isoleucine, to AAC, encoding asparagine. This mutation (I172N) is normally present in the CYP21A pseudogene, so that it may have been transferred to the mutant CYP21B gene by gene conversion. Hybridization of oligonucleotide probes corresponding to this and 2 other mutations normally present in CYP21A demonstrated that 4 out of 20 patients carried the codon 172 mutation; in 1 of these patients, the mutation was present as part of a larger gene conversion involving at least exons 3-6. Gene conversion may be a frequent cause of 21-hydroxylase deficiency alleles due to the presence of 6 chi-like sequences (GCTGGGG) in the CYP21 genes and the close proximity of the CYP21A pseudogene, which has several potentially deleterious mutations. Chiou et al. (1990) also found this mutation on 1 allele in a compound heterozygote. Partanen and Campbell (1991) amplified the full-length genomic P450C21 gene by PCR. The ile172-to-asn mutation in exon 4 was demonstrated. This mutation was observed also by Wedell et al. (1992), who referred to it as ILE173ASN. Speiser et al. (1992) found this mutation in 16% of 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The mutation falls into their group B with 2% enzyme activity and a simple virilizing phenotype. Among 127 patients with 21-hydroxylase deficiency in Sweden, Wedell et al. (1994) found that the ile173-to-asn mutation accounted for 20.8% of 186 unrelated chromosomes. (In the same study, the CYP21 gene was completely absent in 29.8% of chromosomes, the val281-to-leu mutation accounted for 5.4%, and the arg356-to-trp mutation accounted for 3.8%. The most frequent nondeletional mutation was the splice mutation in intron 2, which accounted for 27.7% of the chromosomes.) This mutation is found in 28% of all the cases of simple virilizing type (White et al., 1994). To clarify the molecular basis of nonclassic CAH detectable by neonatal screening in Japan, Tajima et al. (1997) identified 2 sibs and 2 unrelated newborns who were diagnosed with probable nonclassic steroid 21-hydroxylase deficiency. The 2 sibs were found to have 1 allele that had 2 mutations, ile172 to asn and arg356 to trp.