Whole-genome sequencing reveals contribution of rare and common variation to structural kidney and urinary tract malformations
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the commonest cause of kidney failure in children and young adults with over 50 monogenic causes identified, largely in cohorts enriched for familial, syndromic, or consanguineous disease. We sought to better characterise the genomic architecture of these conditions using whole genome sequencing data from 992 unrelated individuals recruited to the UK’s 100,000 Genomes Project. The overall diagnostic yield was 4.3% with family history ( P =7.4×10 −3 ; OR 2.7; 95% CI 1.3-5.4) and extra-renal features ( P =2.0×10 −4 ; OR 3.4; 95% CI 1.8-6.6) independently predicting a monogenic diagnosis. Diagnostic yield was highest in cystic kidney dysplasia (10.7%) and kidney agenesis/hypodysplasia (5.9%). Exome-wide rare variant and genome-wide common variant (minor allele frequency ≥ 0.1%) testing was performed in a subset of 813 patients and 25,205 ancestry-matched controls with significant association detected at rs117473527 ( P =3.93×10 −8 ; OR 3.17; 95% CI 2.10-4.78; MAF 0.02). Heritability analysis estimated common variants explain 23% (standard error 11%) of phenotypic variance in those with European ancestry. Comparison of phenotype-specific genomic risk scores (GRS) demonstrated shared polygenic aetiology between upper urinary tract phenotypes but distinct patterns for both posterior urethral valves (PUV) and bladder exstrophy. A PUV-GRS consisting of 36,106 variants was validated in an independent European cohort of 77 cases and 2,746 controls ( P =1×10 −4 ) accounting for 37% of phenotypic variance. Together, these data demonstrate the importance of non-Mendelian genomic factors in the pathogenesis of CAKUT, evidenced by the fact that only a minority of patients in this large, unselected cohort received a monogenic diagnosis and that a substantial proportion of heritability can be attributed to common variation.
Lay Summary
This study looks at the DNA of patients with congenital anomalies of the kidneys and urinary tract (CAKUT), the most common cause of kidney failure in children. It finds that single gene (monogenic) causes are uncommon, and that genetic testing is more likely to find a cause in people with kidneys that have not formed properly (especially those with cysts), those with affected family members or with involvement of other organ systems. The study also supports the idea that many different common DNA changes (polygenic) together contribute to these conditions, particularly in posterior urethral valves, which is the leading cause of kidney failure in boys. Larger studies are needed to better understand the DNA changes and biological processes involved in kidney and urinary tract development and malformations.
