Position matters and genetic modifiers infuence: A novel COL4A4 variant delays kidney failure in a homozygous Alport syndrome patient and expedites kidney failure in a heterozygous patient
Background: Patients who are heterozygous for COL4A3 or COL4A4 pathogenic variants develop autosomal dominant Alport syndrome (ADAS) generally of milder phenotype compared to patients with biallelic mutations. A common feature is familial microscopic hematuria (FMH), which may or may not progress to added proteinuria and chronic kidney disease (CKD). Methods: We studied clinically and genetically nine patients from four families that segregate FMH, proteinuria and CKD, with clinical suspicion for Alport syndrome. Results: Molecular testing revealed inheritance of a common COL4A4 variant, substituting arginine for glycine-1248, thus disturbing the protein triple-helical domain (COL4A4:c.3742G>C(p.Gly1248Arg). A homozygous patient had the Alport phenotype, including hearing impairment and ocular findings, but a much later age-at-onset of kidney failure (46-years), compared to the age usually seen in patients with other mutations. Importantly, a relative patient, heterozygous for the variant developed kidney failure at 58-years, without extrarenal findings. Conclusions: The delayed kidney failure of the homozygous patient could be attributed to the position of the substitution near a natural interruption of the a4-chain collagenous domain. We hypothesize that the disruption conferred during propagation of the collagen-IV triple-helix is less drastic, affecting less severely the protomer configuration, and maintaining residual activity for network formation in the glomerular basement membrane. The heterozygous patient co-inherited a LAMA5 gene variant that probably acted as a genetic modifier negatively influencing the phenotype. While a limitation of this study is the small patient cohort, the findings support the notion that collagen-IV nephropathies constitute an Alport spectrum condition with diverse manifestations.