Hereditary tubulointerstitial kidney disease (ADTKD) caused by MUC1 mutations is one of the most underdiagnosed genetic kidney disorders worldwide. The reason: over 99 percent of pathogenic MUC1 variants are located in the variable number tandem repeat (VNTR) domain of exon 2, which is inaccessible for standard short-read NGS approaches. 1 As a result, many patients remain undiagnosed despite genetic testing.2
CeGaT closes this diagnostic gap: our VNTR analysis of MUC1 is now integrated into all diagnostic panel and ExomeXtra® tests with a matching indication.
The diagnostic challenge
MUC1-associated ADTKD is typically caused by frameshift variants in the VNTR domain of exon 2. Its repetitive and extended structure prevents standard short-read sequencing approaches from detecting these variants. As a result, affected patients often receive inconclusive reports and remain without a precise diagnosis. This prolongs uncertainty and delays appropriate clinical management.
Identifying pathogenic MUC1 variants not only ends long diagnostic odysseys but also enables appropriate clinical management. A confirmed diagnosis supports risk evaluation for kidney transplantation and allows genetic counseling and testing of at-risk family members.
Clinical indicators
MUC1-associated ADTKD should be considered in cases with:
- unexplained chronic kidney disease (CKD) and autosomal dominant inheritance
- slowly progressive loss of renal function
- bland urinary sediment (absence of hematuria and proteinuria)
- negative or inconclusive prior genetic testing
Case example: diagnostic resolution through VNTR analysis
A 50-year-old male patient with chronic kidney disease stage IV and a positive family history had previously received inconclusive results from standard genetic testing. Through VNTR analysis, CeGaT identified a pathogenic frameshift variant (dupC) in the MUC1 VNTR, providing a definitive diagnosis of ADTKD. The result enabled targeted clinical management and genetic counseling for at-risk family members.
CeGaT’s diagnostic solution
CeGaT combines its proprietary ExomeXtra® enrichment with the VNTyper tool to detect pathogenic variants within the MUC1 VNTR region. Detected variants are confirmed using established SNaPshot assays. This workflow ensures high analytical confidence and supports reliable clinical decisions.
ExomeXtra® combines the benefits of whole exome sequencing and whole genome sequencing with array CGH-like resolution for detecting copy-number variants (CNVs) in a single test.
- Kirby, A. et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nature genetics 2013 Mar;45(3):299-303. doi: 10.1038/ng.2543. Epub 2013 Feb 10.
- Bleyer, A. J. et al. Autosomal Dominant Tubulointerstitial Kidney Disease – MUC1. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2013 Aug 15 [updated 2021 Oct 21].