Journal Article

Pathogenic variants prevalence patients with diabetic kidney disease in Japan: A descriptive study

Sugawara, Yuka, Hirakawa, Yosuke, Hashiba, Toyohiro, Sato, Dai, Inagi, Reiko, Nangaku, Masaomi

2025

Overview

Aims/Introduction The impact of rare pathogenic variants on diabetic kidney disease (DKD) has not been investigated in detail. Previous studies have detected pathogenic variants in 22% of Caucasian patients with DKD; however, this proportion may vary depending on ethnicity and updates to the database. Therefore, we performed a whole‐genome analysis of patients with DKD in type 2 diabetes mellitus in Japan, utilizing a recent database to investigate the prevalence of kidney‐related pathogenic variants and describe the characteristics of these patients. Materials and methods Whole‐genome sequencing was performed, and variants were analyzed following the GATK Best Practices. We extracted data on 790 genes associated with Mendelian kidney and genitourinary diseases. Pathogenic variants were defined based on the American College of Medical Genetics criteria, including both heterozygous and homozygous variants classified as pathogenic or likely pathogenic. Results Among 79 participants, heterozygous pathogenic variants were identified in 27 (34.1%), a higher prevalence than previously reported. No homozygous pathogenic variants were detected. The identified heterozygous pathogenic variants were roughly divided into 23.7% related to glomerulopathy, 36.8% related to tubulointerstitial disease, 10.5% related to cystic disease/ciliopathy, and 28.9% related to others. Diagnostic variants were found in 10 patients (12.7%) in seven genes (ABCC6, ALPL, ASXL1, BMPR2, GCM2, PAX2, and WT1), all associated with autosomal dominant congenital disease. Conclusions This study identified a considerable number of patients with DKD in Japan who carried kidney‐related heterozygous pathogenic variants. These findings suggest potential ethnic differences and highlight the impact of database updates on variant detection. Previous studies have identified pathogenic variants in 22% of Caucasian patients with diabetic kidney disease (DKD); however, this proportion may vary depending on ethnicity and updates to the database. Whole‐genome sequencing of 79 patients with DKD in Japan revealed that 34.1% had kidney‐related heterozygous pathogenic variants, and 12.7% had diagnostic variants for autosomal dominant congenital diseases, a higher prevalence than reported previously. These findings highlight ethnic differences and the importance of database updates in variant detection.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adult / Aged / Body mass index / Bone morphogenetic protein receptor type II / Cardiovascular disease / Creatinine / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - genetics / Diabetic kidney disease / Diabetic Nephropathies - epidemiology / Diabetic Nephropathies - genetics / Diabetic Nephropathies - pathology / Diabetic nephropathy / Diabetic retinopathy / Family medical history / Female / Genomes / Genomic analysis / Humans / Hypertension / Ischemia / Japan - epidemiology / Kidney diseases / Male / Middle Aged / Original / Patients / Pax2 protein / Prevalence / Rare pathogenic variant / Regular / Uric acid / Urine / Variables / Whole Genome Sequencing / Whole‐genome sequence