Abstract
INTRODUCTION: The cause of kidney failure (KF) often remains undetermined despite extensive diagnostic efforts. Given that genetic kidney diseases are underdiagnosed, we conducted a cross-sectional study to investigate the prevalence in patients with KF of undetermined etiology (uKF) using multifaceted genetic screening. METHODS: One hundred twenty-four patients with uKF by age ≤ 50 years previously underwent single-nucleotide polymorphism (SNP)-array and MUC1 analysis. Of these, 114 remained without a genetic diagnosis and underwent whole-genome sequencing (WGS) in 3 consecutive stages as follows: (i) proband-based gene panel analysis; (ii) family-based analysis; and (iii) cohort-based reanalysis, including mitochondrial genome screening. RESULTS: The median age at uKF was 37.5 years, with 92% having adult-onset uKF. WGS identified genetic causes in 26 of 114 (23%). Including all initial 124 families, the combined diagnostic yield was 36 of 124 (29%), with 3 diagnoses from SNP-array, 7 from MUC1 analysis, and 26 from WGS. Six genes (COL4A3/A4/A5, MUC1, NPHP1, and INF2) accounted for nearly 70% of diagnoses. Except for pathogenic MUC1 variants, all were detectable by WGS. A family history of KF was the only predictor of positive genetic screening; however, 18 of 99 patients (18%) without such family history still had a genetic kidney disease. In addition, we propose biallelic variants in complex I assembly factor gene TMEM126B as a cause of adult-onset kidney disease. CONCLUSION: Using WGS, we identified a genetic cause in 23% of patients with uKF at age 50 or younger, resulting in a combined diagnostic rate of 29%. Most pathogenic variants were detectable by WGS.