Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema

Background: Cases of angioedema with no family history but with functionall y low levels of C1 inhibitor and recurrent attacks are often observed. Clin ical and biochemical data do not distinguish these cases from proven inheri ted forms of hereditary angioedema. Objective: We sought to test the hypothesis of de novo mutations in patient s 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 spo radic cases. Nineteen patients with unaffected parents were screened for po int 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 d etected 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 m icrodeletions were found. De novo exon deletions mere detected in 3 additio nal patients,vith Southern blot analysis. Conclusions: De novo Clinhibitor mutations and exon deletions account for a t least 25% of all unrelated cases of angioedema. This finding has implicat ions relevant to the genetic epidemiology and genetic counseling of this di sease. The observation that 5 of the 9 de novo point mutations reproduce pr eviously reported changes underlines the presence of multiple hot spots, tw o of which contain a CpG dinucleotide.