title: The expanding phenotypic spectra of kidney diseases: insights from genetic studies.
abstract: Next-generation sequencing (NGS) has led to the identification of previously unrecognized phenotypes associated with classic kidney disease genes. In addition to improving diagnostics for genetically heterogeneous diseases and enabling a faster rate of gene discovery, NGS has enabled an expansion and redefinition of nephrogenetic disease categories. Findings from these studies raise the question of whether disease diagnoses should be made on clinical grounds, on genetic evidence or a combination thereof. Here, we discuss the major kidney disease-associated genes and gene categories for which NGS has expanded the phenotypic spectrum. For example, COL4A3-5 genes, which are classically associated with Alport syndrome, are now understood to also be involved in the aetiology of focal segmental glomerulosclerosis. DGKE, which is associated with nephrotic syndrome, is also mutated in patients with atypical haemolytic uraemic syndrome. We examine how a shared genetic background between diverse clinical phenotypes can provide insight into the function of genes and novel links with essential pathophysiological mechanisms. In addition, we consider genetic and epigenetic factors that contribute to the observed phenotypic heterogeneity of kidney diseases and discuss the challenges in the interpretation of genetic data. Finally, we discuss the implications of the expanding phenotypic spectra associated with kidney disease genes for clinical practice, genetic counselling and personalized care, and present our recommendations for the use of NGS-based tests in routine nephrology practice.
authors.affiliation: Department of Genetics, Center for Molecular Medicine, KC04.084.2, University Medical Center Utrecht, PO BOX: 85090 3508 AB Utrecht, The Netherlands.
authors.forename: Marijn F
authors.initials: MF
authors.lastname: Stokman
authors.affiliation: Department of Genetics, Center for Molecular Medicine, KC04.084.2, University Medical Center Utrecht, PO BOX: 85090 3508 AB Utrecht, The Netherlands.
authors.forename: Kirsten Y
authors.initials: KY
authors.lastname: Renkema
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Regenerative Medicine Center-Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.affiliation: Department of Paediatric Nephrology, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg BW69120, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.affiliation: Department of Genetics, Center for Molecular Medicine, KC04.084.2, University Medical Center Utrecht, PO BOX: 85090 3508 AB Utrecht, The Netherlands.
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.affiliation: Department of Genetics, Center for Molecular Medicine, KC04.084.2, University Medical Center Utrecht, PO BOX: 85090 3508 AB Utrecht, The Netherlands.
authors.forename: Albertien M
authors.initials: AM
authors.lastname: van Eerde
mesh_terms: D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007674:Kidney Diseases / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics; D010641:Phenotype