Related Experiment Video
Updated: Sep 25, 2025
Generation of Human Kidney Tubuloids from Tissue and Urine
Published on: April 16, 2021
Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial
Eri Okada1,2, Naoya Morisada1,3, Tomoko Horinouchi1
1Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
Introduction:
Autosomal dominant tubulointerstitial kidney disease (ADTKD)-MUC1 is predominantly caused by frameshift mutations owing to a single-base insertion into the variable number tandem repeat (VNTR) region in MUC1. Because of the complexity of the variant hotspot, identification using short-read sequencers (SRSs) is challenging. Although recent studies have revealed the usefulness of long-read sequencers (LRSs), the prevalence of MUC1 variants in patients with clinically suspected ADTKD remains unknown. We aimed to clarify this prevalence and the genetic characteristics and clinical manifestations of ADTKD-MUC1 in a Japanese population using an SRS and an LRS.
Methods:
From January 2015 to December 2019, genetic analysis was performed using an SRS in 48 patients with clinically suspected ADTKD. Additional analyses were conducted using an LRS in patients with negative SRS results.
Results:
Short-read sequencing results revealed MUC1 variants in 1 patient harboring a cytosine insertion in the second repeat unit of the VNTR region; however, deeper VNTR regions could not be read by the SRS. Therefore, we conducted long-read sequencing analysis of 39 cases and detected MUC1 VNTR variants in 8 patients (in total, 9 patients from unrelated families). With the inclusion of family-affected patients (n = 31), the median age at the development of end-stage kidney disease (ESKD) was 45 years (95% CI: 40-40 years).
Conclusion:
In Japan, the detection rate of MUC1 variants in patients with clinically suspected ADTKD was 18.8%. More than 20% of patients with negative SRS results had MUC1 variants detected by an LRS.
Insights
Long-read sequencing improved the detection of MUC1 variants in Autosomal dominant tubulointerstitial kidney disease (ADTKD). This study identified MUC1 variants in 18.8% of Japanese patients, with long-read sequencing revealing cases missed by short-read methods.
Area of Science:
- Genetics
- Nephrology
- Molecular Biology
Background:
- Autosomal dominant tubulointerstitial kidney disease (ADTKD) is often caused by MUC1 frameshift mutations.
- Short-read sequencing (SRS) struggles to identify MUC1 variants due to the complex VNTR region.
- Long-read sequencing (LRS) shows promise for variant detection in complex genomic regions.
Purpose of the Study:
- To determine the prevalence of MUC1 variants in Japanese patients with suspected ADTKD.
- To characterize the genetic and clinical features of ADTKD-MUC1.
- To compare the efficacy of SRS and LRS in detecting MUC1 variants.
Main Methods:
- Genetic analysis using SRS in 48 patients with clinically suspected ADTKD.
- Additional LRS analysis for patients with negative SRS results.
- Clinical data collection and analysis of MUC1 variant carriers.
Main Results:
- SRS identified MUC1 variants in 1 patient; LRS detected variants in 8 additional patients, totaling 9 unrelated families.
- The overall detection rate of MUC1 variants in Japanese patients was 18.8%.
- LRS identified MUC1 variants in over 20% of patients with initially negative SRS results.
Conclusions:
- LRS significantly enhances the detection of MUC1 variants in ADTKD.
- The prevalence of ADTKD-MUC1 in Japan is higher than previously estimated.
- Genetic analysis using both SRS and LRS is crucial for accurate ADTKD-MUC1 diagnosis.
