- Design
- Whole-genome sequencing cohort with association analyses
- Population
- 1,052 unrelated individuals with CAKUT
- Primary outcome
- Monogenic diagnostic yield
- Effect
- 4.9% overall; 11.1% in cystic kidney dysplasia; consanguinity OR 3.0 (1.2-6.9)
Researchers analysed whole-genome sequences from 1,052 unrelated people with congenital anomalies of the kidney and urinary tract in the UK 100,000 Genomes Project.
A monogenic diagnosis was found in 4.9%, rising to 7.4% in kidney agenesis or hypodysplasia and 11.1% in cystic dysplasia. Family history (OR 2.2), consanguinity (OR 3.0) and extra-renal features (OR 3.1) each independently predicted a genetic diagnosis. Common and low-frequency variants explained an estimated 23% of the variation in risk, with a wide interval, and a new risk locus was identified that still needs replication.
Genome sequencing is not a high-yield test for CAKUT as a whole. It is most worth requesting in the patients with the features above, which matters in Indian practice where consanguinity is common in some communities and genetic testing is often self-funded.
- Expect a low genetic diagnostic yield in unselected CAKUT.
- Prioritise genetic testing for patients with family history, consanguinity or extra-renal features.
- Cystic dysplasia and kidney agenesis or hypodysplasia have the highest yield.
- A negative genetic test does not exclude an inherited contribution.
Why it matters
Most of the inherited risk of CAKUT lies outside single genes, so broad testing returns little.
Don't overread it
The new risk locus and polygenic findings need replication.
The statistics, in plain English
Odds ratios of 2 to 3 for each predictor mean these features roughly double or triple the chance of finding a genetic cause, but with a baseline yield of 5%, even a positive predictor leaves most patients without a diagnosis.
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