Detecting Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease.

INTRODUCTION

Autosomal dominant tubulointerstitial kidney disease (ADTKD)- is predominantly caused by frameshift mutations owing to a single-base insertion into the variable number tandem repeat (VNTR) region in . 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 variants in patients with clinically suspected ADTKD remains unknown. We aimed to clarify this prevalence and the genetic characteristics and clinical manifestations of ADTKD- 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 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 VNTR variants in 8 patients (in total, 9 patients from unrelated families). With the inclusion of family-affected patients ( 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 variants in patients with clinically suspected ADTKD was 18.8%. More than 20% of patients with negative SRS results had variants detected by an LRS.