ClinVar Genomic variation as it relates to human health

The most frequent nondeletional mutation found in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (201910) is an A-to-G transition at position -2 in the acceptor splice site of intron 2. As a result of the mutation, an aberrant splice acceptor site is activated 7 bases upstream of the mutation (Higashi et al., 1988). As pointed out by Miller (1996), this mutation, located in intron 2, is 13 bases (not 2) from the splice acceptor site of exon 3. According to the nucleotide numbering system of Higashi et al. (1988), it is residue 655. Miller (1996) noted that this base is normally polymorphic, being either C or A with roughly equal frequency in the normal population. Either a C-to-G or A-to-G mutation at nucleotide -13 causes the severe 21-OH deficiency. This mutation has been detected in patients affected with either the salt-wasting or simple virilizing forms of the disorder (Owerbach et al., 1990; Mornet et al., 1991). White et al. (1994) reported that this mutation represents 22% of the salt-wasting cases, 25% of the simple virilizing cases, and 12% of the nonclassic cases. As reported by Hirschfeld and Fleshman (1969) and Pang et al. (1982), the Yupik Eskimos of western Alaska have the world's highest prevalence of HLA-linked classic congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. The frequency was estimated to be between 1 in 282 and 1 in 490 liveborn infants. Studying 4 patients from 3 apparently unrelated Eskimo families residing in geographically distant villages, Speiser et al. (1992) found that all were homozygous for a substitution of G for A at base 656 in the second intron. They concluded that allele-specific hybridization should be an efficient means of prenatal diagnosis in this isolated population. In the Spanish population, Ezquieta et al. (1995) found this splicing mutation in 30% of 41 mutant chromosomes, making it the most frequent cause of severe CAH in this population. They stated the mutation as an A-to-G change at nucleotide 655 of their clone. During the course of genetic analysis of CYP21 mutations in CAH families, Day et al. (1996) noticed a number of relatives genotyped as nucleotide 656G homozygotes who showed no clinical signs of disease. They proposed that the putative asymptomatic nucleotide 656G/G individuals are incorrectly typed due to a dropout of 1 haplotype during PCR amplification of CYP21. They recommended that for prenatal diagnosis, microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nucleotide 656. Lee et al. (2003) noted that approximately 75% of defective CYP21 genes that cause CAH are generated through intergenic recombination, termed apparent gene conversion, from the neighboring CYP21P pseudogene. Among them, the common intron 2 splice site mutation, which Lee et al. (2003) designated IVS2-12A/C-G, is believed to be derived from this mechanism and is the most prevalent case among all ethnic groups. However, mutation of 707-714delGAGACTAC (613815.0015) rarely exists alone, although this locus is 53 nucleotides away from IVS2-12A/C-G. From the molecular characterization of the mutation of IVS2-12A/C-G combined with 707-714delGAGACTAC in patients with congenital adrenal hyperplasia, Lee et al. (2003) found that it appeared to be in a 3.2- rather than a 3.7-kb fragment generated by Taq I digestion in a PCR product of the CYP21 gene. Interestingly, the 5-prime end region of such a CYP21 haplotype had CYP21P-specific sequences. The authors concluded that the coexistence of these 2 mutations is caused by deletion of the CYP21P, XA (TNXA; see 600985), RP2 (pseudogene of STK19, 604977), and C4B (120820) genes and intergenic recombination in the C4-CYP21 repeat module. Among 370 unrelated alleles from patients in the Netherlands with 21-hydroxylase deficiency, Stikkelbroeck et al. (2003) found this to be the most common point mutation, occurring in 28.1% of alleles. They referred to the mutation as I2G (IVS2-13A/C-G; 656A/C-G). (less)

Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Pregnancy history (present) , Abnormal placenta morphology (present) , Maternal teratogenic exposure (present) , Premature birth (present) , Abnormality of the umbilical cord (present) , Adrenal hyperplasia (present) , Myopia (present) , Anxiety (present) , Depression (present) , Increased susceptibility to fractures (present) , Abnormal sex determination (present) , Abnormality of the female genitalia (present) , Abnormality of reproductive system physiology (present) , Abnormal number of teeth (present) , Tooth malposition (present) (less)