Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Abstract

Over the last two decades, we have extensively studied the genetics of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH) and have performed 8,290 DNA analyses of the CYP21A2 gene on members of 4,857 families at risk for CAH--the largest cohort of CAH patients reported to date. Of the families studied, 1,507 had at least one member affected with one of three known forms of CAH, namely salt wasting, simple virilizing, or nonclassical CAH. Here, we report the genotype and phenotype of each affected patient, as well as the ethnic group and country of origin for each patient. We showed that 21 of 45 genotypes yielded a phenotypic correlation in our patient cohort. In particular, contrary to what is generally reported in the literature, we found that certain mutations, for example, the P30L, I2G, and I172N mutations, yielded different CAH phenotypes. In salt wasting and nonclassical CAH, a phenotype can be attributed to a genotype; however, in simple virilizing CAH, we observe wide phenotypic variability, particularly with the exon 4 I172N mutation. Finally, there was a high frequency of homozygous I2G and V281L mutations in Middle Eastern and Ashkenazi Jewish populations, respectively. By identifying the predominant phenotype for a given genotype, these findings should assist physicians in prenatal diagnosis and genetic counseling of parents who are at risk for having a child with CAH.

Fig. 1.

Common CYP21A2 mutations resulted from CYP21A1P gene microconversion. Of 15 disease-causing CYP21A2 mutations arising from CYP21A1P gene microconversion, 4 are in the promoter, 1 is in the intron, and 10 are in the coding region. For the promoter and intronic mutations, nucleotide changes in the genomic sequence are shown. For mutations in the coding region, nucleotide changes in the genomic and cDNA sequence, as well as the amino acid residue changes in the protein sequence, are listed. The coding sequences are in black boxes, and the UTRs are in gray. The g.655A/C>G mutation on intron 2, the g.707_714delGAGACTAC mutation on exon 3, and the p.I236N, p.V237E and p.M239K cluster mutations on exon 6 are designated as I2G, E3∆8bp, and E6, respectively, in this article.

Fig. 2.

CYP21A2 gene deletion. Due to the high homology between the RP1-C4A-CYP21A1P-TNXA and the RP2-C4B-CYP21A2-TNXB regions, gene rearrangement sometimes occurs because of unequal cross-over during meiosis. This rearrangement causes a 30-kb fragment deletion resulting in a CYP21A1P/CYP21A2 chimera. To date, nine types of chimera (CH1–CH9) with different junction sites have been identified. CYP21A1P and CYP21A2 exons are in open and gray boxes, respectively.

Fig. 3.

Frequency of CYP21A2 genotypes in 1,507 CAH patients. The number of CAH patients with each of the CYP21A2 genotypes (NC, green; SV, blue; SW, red) is shown. This figure should be used in conjunction with Tables S1–S6.

Fig. 4.

Genotype–phenotype association in CAH caused by 21-hydroxylase deficiency. There is a high genotype–phenotype concordance in the V281L, del, E3∆8bp, E6, Q318X, and R356W mutations. In contrast, whereas the P30L mutation is frequently associated with NC, >30% patients carrying the P30L mutation display classical CAH phenotypes. Similarly, although the I172N mutation is usually associated with SV, it is also seen in 23% of SW CAH patients. Likewise, the I2G mutation is mostly associated with SW but is also observed in 20% of SV CAH patients.