Whole-genome sequencing characterizes monogenic and polygenic contributions to structural kidney and urinary tract malformations

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Abstract Introduction Congenital anomalies of the kidneys and urinary tract (CAKUT) are the commonest cause of kidney failure in children and young adults. Over 50 monogenic causes have been identified, however fewer than 20% of patients have a genetic diagnosis identified using targeted or whole exome sequencing. We sought to characterise the genomic architecture of CAKUT using whole genome sequencing (WGS). Methods Using WGS data from 1,052 unrelated individuals with CAKUT recruited to the UK’s 100,000 Genomes Project, we used a panel-based framework to determine diagnostic yield and looked for gene-based enrichment of rare variants exome-wide. We performed sequencing based genome­wide association studies (seqGWAS) and estimated the heritability attributable to common and low-frequency variants. Results The diagnostic yield was 4.9%, increasing to 7.4% in those with kidney agenesis/hypodysplasia and 11.1% in cystic kidney dysplasia. Family history (P=0.02; OR 2.2; 95% CI 1.1-4.4), consanguinity (P=0.01; OR 3.0; 95%CI 1.2-6.9) and extra-renal features (P=1.1×10 - 4 ; OR 3.1; 95% CI 1.7-5.7) independently predicted a monogenic diagnosis. Exome-wide rare variant and genome-wide common and low-frequency variant (minor allele frequency [MAF] ≥ 0.5%) association testing in a subset of 813 patients and 25,205 ancestry-matched controls identified significant association at 6q16.3 (rs117473527; P=4.83×10 - 8 ; OR 3.13; 95% CI 2.08-4.72; MAF 0.01) requiring replication. Common and low-frequency variants were estimated to explain 23% (95% CI 1-45%) of the phenotypic variance observed in CAKUT although this was associated with wide confidence intervals. A genomic risk score for posterior urethral valves was also validated in an independent European cohort of 77 cases and 2,746 controls (P < 0.001). Conclusions Only a minority of patients in this cohort received a monogenic diagnosis, with common and low-frequency variants hypothesised to account for some of this missing heritability. This suggests non-Mendelian genomic factors may be important for the pathogenesi s of CAKUT. Lay Summary This study shows that single-gene causes of isolated and non-familial CAKUT are infrequent, and that genomic testing should be targeted towards those with kidney cysts and/or small kidneys that have not formed properly in the womb. Individuals with a close relative with CAKUT and those with involvement of other organ systems were more likely to receive a genetic diagnosis. These data support a possible polygenic basis for CAKUT, where many common DNA changes cumulatively affect ri sk, particularly in posterior urethral valves, the most common cause of kidney failure in boys. Larger collaborative genomic studies are needed to increase our ability to identify these DNA changes and the mechanisms and pathways important for kidney and urinary tract development.

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