ClinVar Genomic variation as it relates to human health

In a child with Antley-Bixler syndrome and disordered steroidogenesis (ABS1; 201750), Fluck et al. (2004) found compound heterozygosity for a 1370G-A transition in the POR gene leading to an arg457-to-his (R457H) substitution on the maternal allele, and a 731+1G-A change (124015.0006) in the first base of the splice donor site of intron 6 on the paternal allele. The corresponding minigene construct retained intron 6, leading to a premature stop codon. In a female (46,XX) offspring of healthy, unrelated parents of Polish descent with congenital adrenal hyperplasia due to apparent combined deficiency of P450C17 and P450C21 (613571), Arlt et al. (2004) described compound heterozygosity for 2 mutations in the POR gene: A287P (124015.0002) and the R457H mutation. (Arlt et al. (2004) numbered these mutations A284P and R454H, respectively, according to the amino acid position in the protein (GenBank P16435).) The girl was born with clubfeet and ambiguous genitalia, including enlargement of the clitoris and partial labial fusion. Virilization did not progress after birth. Follow-up at 13 years of age showed a marfanoid habitus, scoliosis, arachnodactyly, dysplastic ears, and long, slim limbs. Ovarectomy due to rupture of large ovarian cysts was performed at 14 and 16 years of age. In this family, 5 preceding and 2 subsequent pregnancies resulted in early miscarriages. The unaffected father was heterozygous for A287P; the unaffected mother and younger brother were heterozygous for R457H. Huang et al. (2005) sequenced the POR gene in 29 individuals with a diagnosis of Antley-Bixler syndrome and/or hormonal findings that suggested POR deficiency. Fifteen patients carried POR mutations on both alleles, and 4 carried mutations on only 1 allele. The 34 affected POR alleles included 7 with R457H, in 4 Japanese, 1 African, and 2 white patients. Fukami et al. (2005) identified the R457H mutation in 10 of 16 alleles from 8 Japanese families with skeletal findings of ABS and abnormal genitalia and/or impaired steroidogenesis. R457H was associated with a specific haplotype; Fukami et al. (2005) suggested that the high frequency of R457H in the Japanese is due to a founder effect. Adachi et al. (2006) performed SNP analysis in 5 previously reported patients with POR deficiency and the R457H mutation (4 Japanese and 1 Polish), and found that the non-Japanese patient had the same SNP pattern as Japanese patients, suggesting that R457H is a global founder mutation. (less)

In a child with Antley-Bixler syndrome and disordered steroidogenesis (ABS1; 201750), Fluck et al. (2004) found compound heterozygosity for a 1370G-A transition in the POR gene leading to an arg457-to-his (R457H) substitution on the maternal allele, and a 731+1G-A change (124015.0006) in the first base of the splice donor site of intron 6 on the paternal allele. The corresponding minigene construct retained intron 6, leading to a premature stop codon. In a female (46,XX) offspring of healthy, unrelated parents of Polish descent with congenital adrenal hyperplasia due to apparent combined deficiency of P450C17 and P450C21 (613571), Arlt et al. (2004) described compound heterozygosity for 2 mutations in the POR gene: A287P (124015.0002) and the R457H mutation. (Arlt et al. (2004) numbered these mutations A284P and R454H, respectively, according to the amino acid position in the protein (GenBank P16435).) The girl was born with clubfeet and ambiguous genitalia, including enlargement of the clitoris and partial labial fusion. Virilization did not progress after birth. Follow-up at 13 years of age showed a marfanoid habitus, scoliosis, arachnodactyly, dysplastic ears, and long, slim limbs. Ovarectomy due to rupture of large ovarian cysts was performed at 14 and 16 years of age. In this family, 5 preceding and 2 subsequent pregnancies resulted in early miscarriages. The unaffected father was heterozygous for A287P; the unaffected mother and younger brother were heterozygous for R457H. Huang et al. (2005) sequenced the POR gene in 29 individuals with a diagnosis of Antley-Bixler syndrome and/or hormonal findings that suggested POR deficiency. Fifteen patients carried POR mutations on both alleles, and 4 carried mutations on only 1 allele. The 34 affected POR alleles included 7 with R457H, in 4 Japanese, 1 African, and 2 white patients. Fukami et al. (2005) identified the R457H mutation in 10 of 16 alleles from 8 Japanese families with skeletal findings of ABS and abnormal genitalia and/or impaired steroidogenesis. R457H was associated with a specific haplotype; Fukami et al. (2005) suggested that the high frequency of R457H in the Japanese is due to a founder effect. Adachi et al. (2006) performed SNP analysis in 5 previously reported patients with POR deficiency and the R457H mutation (4 Japanese and 1 Polish), and found that the non-Japanese patient had the same SNP pattern as Japanese patients, suggesting that R457H is a global founder mutation. (less)