Autosomal dominant tubulointerstitial kidney disease cosegregating with COL4A4:p.G545A in Turkish Cypriot families with kidney failure

Abstract

Abstract Chronic kidney disease (CKD) is a global health priority with over 850 million people affected. The starting point for improving outcome must be to diagnose the primary renal disease and in low and middle income countries ‘unknown aetiology’ accounts for the majority of diagnoses. In Cyprus, familial kidney disease is very common. Using next-generation sequencing, we found that a common polymorphism (COL4A4:p.G545A), hitherto considered to be benign or hypomorphic, was present in 5 of 53 Turkish Cypriot families with kidney disease and a glomerular phenotype (at least one person with haematuria and/or proteinuria). Therefore, we tested 49 further families with kidney disease using a restriction fragment length polymorphism assay. From this total of 102 families, we showed that this variant was present in 12 of 85 families (14%) with some evidence of glomerular disease and none of 17 with chronic kidney disease lacking these features. Co-segregation analyses indicated that the variant co-segregated with disease more than would be expected by chance. These families have an autosomal dominantly inherited susceptibility to kidney disease associated with variable and intermittent microscopic haematuria, proteinuria < 1 g/day until the eGFR falls below 30 ml/min. End-stage kidney disease occurred in 17% of those affected at a median of 66 years. The presentation is more characteristic of a tubulointerstitial kidney disease and represents a tubular phenotype of Alport spectrum nephropathy.