Frequent de novo mutations and exon deletions in the C1 inhibitor gene of patients with angioedema

Background: Cases of angioedema with no family history but with functionally low levels of C1 inhibitor and recurrent attacks are often observed. Clinical and biochemical data do not distinguish these cases from proven inherited forms of hereditary angioedema. Objective: We sought to test the hypothesis of de novo mutations in patients affected by angioedema without a family history of the disease. Methods: Among 137 independent kindreds followed for hereditary angioedema, 45 (32.8%) patients with early onset of the disease were registered as sporadic cases. Nineteen patients with unaffected parents were screened for point mutations and microdeletions-insertions by using fluorescence-assisted mismatch analysis. The biologic paternity of these patients was verified by determining their alleles at 4 microsatellite loci. Gross deletions were detected with Southern blot analysis. Results: C1 inhibitor plasma levels measured in both parents of 24 sporadic patients were normal in all but 3 patients. Among the 19 patients studied at the DNA level, 9 de novo single nucleotide substitutions and 6 de novo microdeletions were found. De novo exon deletions were detected in 3 additional patients with Southern blot analysis. Conclusions: De novo C1 inhibitor mutations and exon deletions account for at least 25% of all unrelated cases of angioedema. This finding has implications relevant to the genetic epidemiology and genetic counseling of this disease. The observation that 5 of the 9 de novo point mutations reproduce previously reported changes underlines the presence of multiple hot spots, two of which contain a CpG dinucleotide.