Autosomal dominant kidney disease phenocopying hypertensive nephropathy in Turkish Cypriot Families

Abstract

Abstract Background In Cyprus, chronic kidney disease (CKD) is very common and often presents as a haematuric nephropathy caused by autosomal dominant pathogenic variants in the COL4A3 or COL4A4 genes. We investigated 57 Turkish Cypriots (TCs) with familial CKD for pathogenic variants in the COL4A3 and COL4A4 genes. Methods Probands from 53 families underwent massive parallel DNA sequencing using a glomerular gene panel for familial haematuria (COL4A3, COL4A4, COL4A5, CFHR5, and FN1), and whole exome sequencing (WES) was performed for 24 families. Twenty families were subjected to both procedures. Variants of interest were validated and tested in other family members by Sanger DNA sequencing or polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) and agarose gel electrophoresis. Results The diagnostic yield from these families was disappointing, and likely pathogenic variants were identified in only 12 of the 57 patients (genes, including COL4A3 (3), COL4A4 (2), and COL4A5 (2)), leaving 45 unsolved families. Among the latter, a common missense variant (COL4A4:p. G545A), was present in four of the 45 unsolved and one of the solved families. Subsequently, we examined at least one member from a total of 85 families with evidence of familial kidney disease and a probable glomerular phenotype (at least one person with hematuria or proteinuria) and found 12 families (14%) with the p.G545A variant, which seemed to cosegregate with renal disease more often than would be expected by chance. All these families demonstrate an autosomal dominant (AD) inherited susceptibility to kidney disease associated with hypertension, variable and intermittent microscopic hematuria, and minimal proteinuria that remains at < 1 g/day until the estimated glomerular filtration rate (eGFR) falls below 30 ml/min, after which it may increase. Conclusions We suggest that COL4A4:p. G545A may play a permissive polygenic role in a novel renal condition that phenocopies ‘hypertensive nephropathy’. This variant may be a common contributor to renal failure in the eastern Mediterranean region, thus justifying further investigation in appropriate families.