ClinVar Genomic variation as it relates to human health

In 3 unrelated cases of autosomal recessive chronic granulomatous disease-1 (CGD1; 233700), Casimir et al. (1991) identified a homozygous 2-bp deletion (c.75delGT) at a GTGT tandem repeat in the NCF1 gene, corresponding to the acceptor site of the first intron-exon junction (between IVS1 and exon 2). The authors suggested that slippage of the DNA duplex at this site may contribute to the high frequency of defects in this gene. In 2 unrelated patients (KS and SR) with CGD, Volpp and Lin (1993) identified a c.75delGT mutation in the NCF1 gene, resulting in a frameshift and premature termination at base 165. Patient KS was homozygous for the GT deletion, which occurred within the sequence TATGTGTA (bases 70-78). The other patient (SR) was compound heterozygous for c.75delGT and a 1-bp deletion (c.502delG; 608512.0002), which results in a frameshift and premature termination at base 605. Patient SR had previously been reported by Clark and Klebanoff (1978). Volpp and Lin (1993) demonstrated that the transfection of NCF1 cDNA into p47-phox-deficient cell lines resulted in the generation of normal levels of superoxide and readily detectable cytosolic enzyme. Gorlach et al. (1997) found that in each of 34 consecutive unrelated normal individuals, both the normal and mutant delta-GT sequences were present in genomic DNA. Further study revealed that this finding was due to the p47-phox pseudogene containing the delta-GT mutation. This close linkage, together with the presence within each gene of multiple recombination hotspots, suggested that the predominance of the delta-GT mutation in this autosomal recessive form of CGD is caused by recombination events between the wildtype gene and the pseudogene(s). Gene conversion events between homologous genes and their pseudogenes had been described in the pathogenesis of several genetic disorders, such as 21-hydroxylase deficiency (201910), von Willebrand disease (193400), and Gaucher disease (230800). Roesler et al. (2000) performed sequence analysis of 28 unrelated, racially diverse patients with the p47-phox-deficient form of CGD and 37 healthy individuals. In 25 patients, the CGD deletion in exon 2 was present in all alleles. Three patients and all healthy individuals contained GTGT and delta-GT sequences, the latter being a characteristic of the NCF1 pseudogene. A total of 22 patients carried additional pseudogene-specific intronic sequences on all alleles, either only in intron 1 or in intron 1 and intron 2, which led to different types of chimeric DNA strands. Roesler et al. (2000) concluded that recombination events between the NCF1 gene and its highly homologous pseudogenes result in the incorporation of delta-GT into the NCF1 gene, thereby leading to the high frequency of GT deletion in CGD patients with the p47-phox-deficient form. Unlike other CGD subtypes, in which there is great heterogeneity among mutations, 97% of affected alleles in patients with p47-phox deficiency carry the 2-bp deletion in the NCF1 gene (Noack et al., 2001). (less)