Digenic variations of human COL4A3 and COL4A4 genes result in early onset renal failure

Type IV collagen protein is formed by the interaction of α3. α4. α5 chains and is encoded by COL4A3, COL4A4 and COL4A5 genes located on the chromosome 2 and the X-chromosome. Pathogenic variations in these genes are reported to be associated with the Alport sydrome (OMIM#104200) and follow the three classic Mendelian inheritance patterns; i) autosomal recessive, ii) autosomal dominant and iii) X-linked inheritance. Recently, with the emergence of massively parallel sequencing, a digenic etiology of Alport syndrome has been postulated, characterized by hematuria, proteinuria, end stage renal disease and chronic kidney failure often accompanied by the sensorineural deafness. Here, we report on the case of an 18 months old girl with clinical features of early onset renal failure in absence of any known cause. Patient was investigated using targeted massively parallel sequencing which revealed two novel variants in COL4A3 and COL4A4 genes. The variants were confirmed with Sanger sequencing as de novo missense variations c.4145G > T (p.Gly1382Val) and c.2956C > T (p.Pro986Ser) in the COL4A3 and COL4A4 genes, respectively. The variants are neither reported in population databases like 1000 Genomes, ExAC, etc. nor in Clinvar and are predicted to be disease causing by mutation prediction software. The HMM-based haplotype phasing revealed that the digenic variations identified are likely to be in cis. Overall, the findings suggest that the potential variants identified may explain the disease phenotype of the patient.