ClinVar Genomic variation as it relates to human health

A G-to-C transversion in intron 8 of the DHCR7 gene results in a splice site defect and a null mutation, and is the most common mutant allele in Smith-Lemli-Opitz syndrome (SLOS; 270400) (Wright et al., 2003). In cell line A2SLO from a patient with severe SLOS, Wassif et al. (1998) identified a 134-bp insertion between nucleotides 788 and 789 of the DHCR7 gene. The insertion resulted in a frameshift, starting at amino acid 263, that precluded translation of the highly conserved carboxyl end of the protein. The cell line was homozygous for the insertion. In a patient with severe SLOS, the first child of unrelated parents, Waterham et al. (1998) found homozygosity for a 134-bp insertion in the DHCR7 gene after nucleotide 963. Yu et al. (2000) noted that the IVS8-1G-C mutation results in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop. The more severe phenotype in this patient was consistent with the fact that the insertion occurred in a region strongly conserved among sterol reductases. Both parents were heterozygous for the insertion. Waterham et al. (1998) found the 134-bp insertion in compound heterozygous state in a child with SLOS, the other allele carrying the trp248-to-cys mutation (602858.0008) in the DHCR7 gene. Among 16 patients with severe SLOS (severity score greater than 50), Witsch-Baumgartner et al. (2000) found that 14 of 32 mutant alleles carried an IVS8-1G-C mutation in the DHCR7 gene. Yu et al. (2000) reported a simple PCR-based restriction endonuclease digestion assay for the rapid detection of this mutation, which they identified in 21 of 66 alleles. The authors concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S. Witsch-Baumgartner et al. (2001) detected the IVS8-1G-C mutation on 25 of 118 alleles (21.2%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected (Great Britain, 34.1% of alleles; Germany/Austria, 20.5%; Poland, 3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 13 IVS8-1G-C chromosomes shared the same haplotype and therefore provided evidence for a founder effect. One IVS8-1G-C mutation was present in cis with a T93M mutation (602858.0009) on a different haplotype. As one of the other T93M alleles was also characterized by this haplotype, the double mutant was consistent with a recombination event. Krakowiak et al. (2000) detected this mutation in compound heterozygosity with thr289 to ile (602858.0015) in 2 brothers with SLOS. Nowaczyk et al. (2001) found that the boys' female first cousin carried the IVS8-1G-C/T289I genotype as well. The 2 unrelated mothers were carriers of the IVS8-1G-C mutation. Nowaczyk et al. (2001) found the IVS8-1G-C mutation in homozygous state in a fetus and 2 newborns with severe SLOS and holoprosencephaly. They stated that of the 6 previously reported severely affected newborns with SLOS who were homozygous for this mutation, none had HPE. The IVS8-1G-C mutation is the most frequently identified mutant allele, accounting for approximately one-third of reported SLOS alleles. Wright et al. (2003) screened for this mutation in African Americans and found a carrier frequency of 0.73% (10 of 1378), which predicted a homozygosity incidence of 1 of 75,061. They suggested that it is likely that the IVS8-1G-C allele appeared in the African American population through admixture. Witsch-Baumgartner et al. (2001) suggested that this mutation is a founder mutation that arose in the British Isles. Scalco et al. (2005) detected the IVS8-1G-C mutation on 10 of 28 alleles (36%) in a study of 14 SLOS patients from Brazil. In 7 patients, the IVS8-1G-C mutation was found in compound heterozygosity with the T93M mutation (602848.0009). By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the IVS8-1G-C mutation, which they called 964-1G-C, appeared about 3,000 years ago in northwest Europe. (less)