Background and objectives: Alport syndrome (AS) is a predominantly X-linked hereditary nephritis associated with high-tone, sensorineural deafness and characteristic eye signs. Clinical diagnostic criteria were defined in 1988. Most cases result from mutations in the X-linked collagen gene COL4A5, with mutations in the autosomal genes COL4A3 and COL4A4 on chromosome 2 accounting for the rest. Mutation analysis of COL4A5 with a combination of sequencing and multiplex ligation-dependent probe amplification has been available for several years. The objective of this study was to determine the utility of clinical diagnostic criteria in identifying patients likely to have a COL4A5 mutation.
Design, setting, participants, & measurements: Clinical information was available on 206 patients whose DNA was received for testing between 1994 and June 2008; predictive tests for a known familial mutation, samples from duplicate family members, and incompletely screened samples were excluded. One hundred and twenty-eight patients (62.1%) had a pathogenic COL4A5 mutation.
Results: The mutation detection rate in families fulfilling zero, one, two, three, or four diagnostic criteria was 0%, 18%, 64%, 89%, and 81%, respectively. Sixty-seven percent of patients with COL4A5 mutations meeting only two diagnostic criteria had not had a complete clinical assessment. In two thirds of families meeting four diagnostic criteria without an identified COL4A5 mutation, autosomal inheritance was confirmed or suspected.
Conclusions: The authors recommend COL4A5 analysis in any patient meeting at least two clinical diagnostic criteria. COL4A3 and COL4A4 analysis should be considered if a COL4A5 mutation is not detected and primarily if autosomal inheritance is suspected.