LAUSR

Although often considered a single-entity, chronic kidney disease (CKD) comprises many pathophysiologically distinct disorders that result in persistently abnormal kidney structure and/or function, and encompass both monogenic and polygenic aetiologies. Rare inherited forms of CKD frequently span diverse phenotypes, reflecting genetic phenomena including pleiotropy, incomplete penetrance and variable expressivity. Use of chromosomal microarray and massively parallel sequencing technologies has revealed that genomic disorders and monogenic aetiologies contribute meaningfully to seemingly complex forms of CKD across different clinically defined subgroups and are characterized by high genetic and phenotypic heterogeneity. Investigations of prevalent genomic disorders in CKD have integrated genetic, bioinformatic and functional studies to pinpoint the genetic drivers underlying their renal and extra-renal manifestations, revealing both monogenic and polygenic mechanisms. Similarly, massively parallel sequencing-based analyses have identified gene- and allele-level variation that contribute to the clinically diverse phenotypes observed for many monogenic forms of nephropathy. Genome-wide sequencing studies suggest that dual genetic diagnoses are found in at least 5% of patients in whom a genetic cause of disease is identified, highlighting the fact that complex phenotypes can also arise from multilocus variation. A multifaceted approach that incorporates genetic and phenotypic data from large, diverse cohorts will help to elucidate the complex relationships between genotype and phenotype for different forms of CKD, supporting personalized medicine for individuals with kidney disease. An increasing body of evidence suggests that genomic disorders and monogenic aetiologies contribute meaningfully to seemingly complex forms of chronic kidney disease (CKD). This Review describes rare genetic causes of CKD and the genetic and phenotypic complexity of this group of disorders, and discusses novel approaches to help to address the challenges posed by the complexity of CKD. Chronic kidney disease (CKD) is a complex disorder comprising many rarer, pathophysiologically distinct conditions that encompass both monogenic and polygenic forms, which share the common feature of leading to persistent anomalies in renal structure and/or function. Rare hereditary causes of CKD often show high phenotypic heterogeneity, which can result from pleiotropy, incomplete penetrance or variable expressivity. Microarray and massively parallel sequencing studies have shown that both genomic disorders and monogenic diseases account for a meaningful proportion of cases across different clinical subtypes of CKD. Copy number variants at the 17q12, 22q11.2 and 16p11.2 loci are recurrent genomic disorders among patients with CKD and display diverse and highly variable multiorgan manifestations, which can reflect gene dosage sensitivity and epistatic and epigenetic effects. Although classically considered to be clinically homogeneous, common monogenic causes of CKD, such as autosomal-dominant polycystic kidney disease, type IV collagen-associated nephropathy and autosomal-dominant tubulointerstitial kidney disease, display variable penetrance and expressivity, in part due to gene- and allele-level variation. Multilocus variation, involving variants for multiple genetic conditions, can confer complex phenotypes and has been detected in at least 5% of positive cases from genome-wide testing. Novel techniques that integrate genetic sequencing, experimental assays and clinical data, such as reverse phenotyping, functional screening of potentially pathogenic variants, and genetic and phenotypic risk scores, will support greater understanding of the phenotypic complexity of different forms of CKD.