Hashiba Toyohiro, Sugawara Yuka, Hirakawa Yosuke, Sato Dai, Inagi Reiko, Nangaku Masaomi
Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
J Diabetes Investig. 2025 Jul;16(7):1263-1273. doi: 10.1111/jdi.70041. Epub 2025 Apr 8.
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.
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.
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.
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.
目的/引言：罕见致病变异对糖尿病肾病（DKD）的影响尚未得到详细研究。先前的研究在22%的白种人DKD患者中检测到致病变异；然而，这一比例可能因种族和数据库更新而有所不同。因此，我们利用最新数据库对日本2型糖尿病患者中的DKD患者进行了全基因组分析，以调查肾脏相关致病变异的患病率，并描述这些患者的特征。
进行全基因组测序，并按照GATK最佳实践分析变异。我们提取了与孟德尔肾脏和泌尿生殖系统疾病相关的790个基因的数据。根据美国医学遗传学学会的标准定义致病变异，包括分类为致病或可能致病的杂合和纯合变异。
在79名参与者中，27人（34.1%）被鉴定出杂合致病变异，患病率高于先前报道。未检测到纯合致病变异。鉴定出的杂合致病变异大致分为23.7%与肾小球病相关、36.8%与肾小管间质疾病相关、10.5%与囊性疾病/纤毛病相关以及28.9%与其他疾病相关。在10名患者（12.7%）中发现了七个基因（ABCC6、ALPL、ASXL1、BMPR2、GCM2、PAX2和WT1）的诊断性变异，所有这些基因都与常染色体显性先天性疾病相关。
本研究在日本鉴定出相当数量携带肾脏相关杂合致病变异的DKD患者。这些发现表明可能存在种族差异，并突出了数据库更新对变异检测的影响。
