Variant Interpretation in Monogenic Renal Diseases

The Power of Variant Interpretation in Monogenic Renal Conditions

Introduction

Renal diseases represent a major global health burden. They range from common conditions, such as diabetic nephropathy, to rare inherited disorders that progress to kidney failure.

While many kidney diseases are multifactorial, a critical subset are monogenic renal diseases—conditions caused by mutations in a single gene. These disorders are often difficult to diagnose because they are rare and frequently overlap in presentation with other renal conditions.

Advances in high-throughput genomic sequencing and variant interpretation bioinformatics are changing this landscape. These tools now support more accurate diagnosis, prognosis, and clinical management of inherited kidney disease.

What Are Monogenic Renal Diseases?

Monogenic renal diseases affect different structures of the kidney and arise from pathogenic variants in a single gene.

Prevalence highlights:

• • Up to 10% of adults with end-stage renal disease (ESRD)
  • Up to 70% of children with ESRD have an underlying genetic cause.
    
    

Key Examples of Monogenic Renal Disease

Alport Syndrome & Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

Disease	Characterized By	Caused By Variants In
Alport Syndrome	Hematuria Proteinuria Hearing loss	COL4A3 COL4A4 COL4A5
ADTKD (a group of rare disorders)	Interstitial fibrosis Progressive kidney failure	UMOD MUC1

Clinical insight:
Alport syndrome is a progressive hereditary nephropathy. Rather than being strictly classified by inheritance pattern, modern guidelines increasingly view Alport syndrome as a spectrum of COL4-related nephropathies. Even heterozygous carriers—previously labeled as having “benign familial hematuria”—are now recognized as having a risk of disease progression.

Diagnostic challenge:
ADTKD-MUC1 is particularly difficult to detect because the pathogenic variant usually involves a cytosine insertion within a complex variable number tandem repeat region. Standard next-generation sequencing (NGS) often misses this mutation, requiring specialized mass probe assays or long-read sequencing.

Feature	Alport Syndrome (COL4-Related)	ADTKD (UMOD, MUC1, etc.)
Primary Genes	COL4A3, COL4A4, COL4A5	UMOD, MUC1, REN, SEC61A1
Primary Structure Affected	Glomerular Basement Membrane (GBM)	Renal Tubules & Interstitium
Inheritance Patterns	X-linked (most common), AR, AD	Autosomal Dominant (AD)
Urinary Findings	Active: Microscopic hematuria (blood) and significant proteinuria.	Bland: Minimal protein, usually no blood in the urine.
Key Clinical Markers	Early onset hearing loss and ocular changes (lenticonus).	Early-onset Gout and hyperuricemia (especially in UMOD).
Kidney Biopsy	“Basket-weave” appearance of the GBM on electron microscopy.	Non-specific interstitial fibrosis; often requires genetic testing for diagnosis.
Disease Progression	Often rapid; high risk of ESRD in young males (X-linked).	Slow and progressive; ESRD typically reached between ages 30–60.

While Alport Syndrome is often caught via standard gene panels because the COL4 genes are well-mapped, ADTKD (specifically the MUC1 subtype) is frequently missed. This is because the MUC1 mutation involves a complex “repeat” section of DNA that standard sequencing tools struggle to read. If a patient has a strong family history of gout and kidney failure but a “negative” genetic panel, specialized MUC1 testing is often the next logical step.

The Rise of Genomic Data in Nephrology

Nephrology is shifting from a “biopsy-first” approach to a “genetics-first” model.

• • Kidney biopsies provide a snapshot of existing damage
  • They cannot always distinguish between conditions such as:
    • Focal Segmental Glomerulosclerosis (FSGS)
    • Alport syndrome

By contrast, sequencing technologies, including whole-exome sequencing (WES) and whole-genome sequencing (WGS), enable detection of:

• • Non-coding variants
  • Structural rearrangements that were previously inaccessible.
    
    

Variant Interpretation: From Raw Data to Clinical Insight

What standards are used?

Interpretation follows:

• • ACMG/AMP guidelines
  • Disease-specific refinements from ClinGen Kidney Disease Specialist Panels

Core Steps in Variant Interpretation

• • Frequency assessment
    Using population databases such as gnomAD v4 to confirm rarity
  • In silico prediction
    Tools include:
    • SIFT
    • PolyPhen-2
  • Segregation and phenotyping
    Correlating genetic findings with clinical features
    (e.g., a PKD1 variant with renal cysts)