- Design
- Whole-genome sequencing cohort with rare- and common-variant association analyses
- Population
- 1,052 unrelated individuals with CAKUT, UK 100,000 Genomes Project
- Primary outcome
- Monogenic diagnostic yield
- Effect
- 4.9% overall; 11.1% cystic dysplasia; consanguinity OR 3.0 (1.2–6.9)
A Kidney International study (21 September) analysed whole-genome sequences from 1,052 unrelated people with congenital anomalies of the kidney and urinary tract (CAKUT) in the UK 100,000 Genomes Project.
The monogenic diagnostic yield was 4.9% overall, 7.4% in kidney agenesis or hypodysplasia and 11.1% in cystic kidney dysplasia. A genetic diagnosis was more likely with a family history (OR 2.2), consanguinity (OR 3.0) or extra-renal features (OR 3.1). Common and low-frequency variants were estimated to explain about 23% of variation, with wide uncertainty, and a polygenic risk score for posterior urethral valves was validated in a separate cohort.
For clinicians the message is targeting. Genetic testing is most worthwhile in cystic dysplasia, syndromic presentations, familial cases and consanguineous families — the last of which is relevant in parts of India. Most CAKUT will not have a single-gene explanation.
- Offer genetic testing when CAKUT is cystic, bilateral, syndromic or familial
- Ask specifically about consanguinity and family history of kidney disease
- Look for extra-renal features such as diabetes, genital tract anomalies or hearing loss (HNF1B, PAX2)
- Plan life-long CKD follow-up; many patients reach kidney replacement therapy in adulthood
Why it matters
It sets realistic expectations for genetic testing in the commonest cause of kidney failure in young people.
Don't overread it
The cohort was predominantly UK-based, and yields may differ in populations with more consanguinity.
The statistics, in plain English
A 4.9% yield means about 1 in 20 patients got a single-gene diagnosis. Odds ratios of 2–3 for family history, consanguinity and extra-renal features show where to focus testing. The 23% heritability estimate has an interval from 1% to 45%, so it is highly uncertain.
Read the rest in the app
You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.
Scan to keep reading on your phone. No account needed to start.
Tomorrow morning, before your first patient
One edition a day for nephrology, written by the desk, every claim tied to its paper. Six minutes.
Get the app — free