Autosomal dominant tubulointerstitial kidney disease

The kidney disease your gene panel missed.

ADTKD-MUC1 causes slow, silent kidney failure across every generation of a family. The causal variant sits inside a repeat region that short-read sequencing cannot read — so the panel comes back negative, and the family keeps being told nobody knows why.

The referral pathway What the disease looks like

Gene: MUC1 · chromosome 1q22
Inheritance: Autosomal dominant
Sediment: Bland — no protein, no blood

<1%

of MUC1 variants are identified by clinically available multigene kidney panels.

46 yrs

median age at kidney failure, with a reported range of 20 to 70 years.

50%

risk for each child of an affected parent. Penetrance is complete.

Why it hides

A negative panel is not a negative result.

The pathogenic variant in ADTKD-MUC1 is usually a single cytosine inserted into a 7-cytosine tract inside the MUC1 VNTR — a long, GC-rich, highly repetitive stretch of the gene. Massively parallel sequencing cannot align reads across it, so the region is effectively invisible on a standard panel or exome.

Read a negative kidney gene panel in a family with dominant, bland-sediment CKD as incomplete, not reassuring. Detecting MUC1 requires an assay built for the VNTR: targeted analysis of the cytosine tract, long-read SMRT sequencing, or VNTR amplicon sequencing.

Recognition

Four findings that should raise suspicion.

No single feature is specific. Together, they are close to diagnostic — and they are all available from a chart, a family history, and a urinalysis.

Autosomal dominant family history

CKD in one parent and, typically, an affected relative in each preceding generation. Penetrance is complete; each child of an affected parent carries a 50% risk. De novo variants do occur, so a negative family history does not exclude the diagnosis.

In plain terms — Kidney failure shows up in every generation — a parent, a grandparent, an aunt, a cousin.

Bland urinary sediment

Minimal or absent hematuria. Proteinuria under 500 mg/24h until advanced CKD. The urinalysis is conspicuously unremarkable relative to the degree of functional loss — this discordance is the single most useful bedside clue.

In plain terms — The urine test looks normal, even though the kidneys are failing. That mismatch is the clue.

Normal or small kidneys on imaging

Ultrasound is normal or shows symmetrically small, echogenic kidneys. Occasional simple cysts may be present but never meet ADPKD criteria. Imaging cannot establish or exclude the diagnosis.

In plain terms — An ultrasound or scan will not find this. The kidneys usually look ordinary.

Slow, relentless decline without a cause

A linear eGFR trajectory over decades, absent diabetes, significant hypertension, glomerulonephritis, or obstruction. Median age at kidney failure is 46 years, with a reported range of 20 to 70 years, and eGFR is already below 90 mL/min/1.73m² in roughly half of carriers by age 15.

In plain terms — Kidney function drops steadily for years with no diabetes, no infection, no explanation.

Continue to the disease for subtypes and natural history, or straight to the referral pathway.