Expanding the phenotypic spectrum for alport syndrome and distinguishing phenocopies in genetic kidney disease.

Aim: To describe the phenotypic spectrum in patients with diagnostic type 4 collagen variants, and to determine phenocopies of Alport Syndrome (AS). Background(s): AS is the second most common form of genetic kidney disease (GKD). Recently, Medicare approved testing for the three genes associated with AS. Pursuing genetic diagnosis has important clinical implications. Method(s): We compared the suspected diagnosis prior to ES with the genomic diagnosis in patients with suspected AS from a cohort of 204 patients with suspected GKD. We also compared the suspected diagnosis to the molecular diagnosis in patients who were found to have type 4 collagen variants following ES. Result(s): 80/204(39%) had diagnostic variants in genes related to kidney disease. 26/80(33%) had diagnostic type 4 collagen variants. Most patients (n = 13) had autosomal dominant (AD) COL4A3/4 nephropathy. Eleven had X-Linked dominant AS and 2 had autosomal recessive AS. ES reclassified the diagnosis in 7/26(27%) of patients with type 4 collagen variants. Furthermore, 3 patients who had clinical symptoms suspicious of AS were found to have an alternate diagnosis following ES (2 had X-linked recessive Dent Disease and 1 had AD hypoparathyroidism, sensorineural deafness and renal dysplasia). Conclusion(s): ES revealed type 4 collagen variants in 6 patients with alternate clinical diagnoses suspected at referral. Three additional patients who were thought to have AS were subsequently given an alternate diagnosis. We suggest that AS is underdiagnosed, and testing should be considered in patients with a suspected monogenic cause of hematuria. We also highlight the importance of expanding analysis to additional genes in the evaluation of patients with suspected AS, in addition to those reimbursed by Medicare. ES allows easier subsequent reanalysis of genomic data.