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

Monogenic and polygenic contributions to CAKUT explored by whole-genome sequencing: panel-based diagnostic yield, association of rare and common variants, and a polygenic risk score for posterior urethral valves

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the commonest cause of kidney failure in children and young adults, and over 50 monogenic causes are known, yet fewer than 20% of patients receive a genetic diagnosis through targeted or exome sequencing. The authors analysed whole-genome sequencing (WGS) of 1,052 unrelated individuals with CAKUT recruited to the UK 100,000 Genomes Project, using a panel-based framework to determine diagnostic yield, then testing for exome-wide enrichment of rare variants, for sequencing-based genome-wide associations (seqGWAS) and for the heritability attributable to common and low-frequency variants. The overall diagnostic yield is 4.9%, rising to 7.4% in kidney agenesis/hypodysplasia and 11.1% in cystic kidney dysplasia; family history (odds ratio 2.2; 95% CI 1.1 to 4.4), consanguinity (3.0; 1.2 to 6.9) and extra-renal features (3.1; 1.7 to 5.7) independently predict a monogenic diagnosis. In a subset of 813 patients and 25,205 ancestry-matched controls, a genome-wide significant association appears at 6q16.3 (rs117473527; odds ratio 3.13; 95% CI 2.08 to 4.72; P = 4.8 × 10⁻⁸) but requires replication, and common and low-frequency variants are estimated to explain 23% of the phenotypic variance, with a wide confidence interval (95% CI 1 to 45%). A polygenic risk score for posterior urethral valves was constructed and validated in an independent European cohort of 77 cases and 2,746 controls, and the authors conclude that the monogenic diagnostic yield is only 4.9% in this cohort, with common and low-frequency variants potentially accounting for part of the missing heritability.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A yield of 4.9% on whole-genome sequencing of 1,052 patients is a reminder that most CAKUT have no monogenic cause identified with a panel-based framework, and that diagnostic expectations should be calibrated accordingly in consultation; the independent predictors (family history, consanguinity, extra-renal features) help identify patients in whom this yield is higher. The polygenic part should be read with caution: the 6q16.3 locus awaits replication, the confidence interval of the heritability attributed to common variants runs from 1 to 45%, and the score for posterior urethral valves was validated in only 77 cases. The 4.9% yield is that of a panel-based analysis framework; the abstract does not say what a broader interpretation of these genomes would yield.

Analysis by Dr Thibaut Benquey