Diagnostic Yield of Whole-Genome Sequencing in Patients With Kidney Failure of Undetermined Etiology at Age 50 Years or Younger

Abstract Introduction The cause of kidney failure often remains undetermined despite extensive diagnostic efforts. As genetic kidney diseases are underdiagnosed, we conducted a cross-sectional study to investigate the prevalence in patients with kidney failure of undetermined etiology (uKF) using multi-faceted genetic screening. Methods 124 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 three consecutive stages: 1) proband-based gene panel analysis, 2) family-based analysis, and 3) cohort-based reanalysis, including mitochondrial genome screening. Results The median age of uKF was 37.5 years, with 92% having adult-onset uKF. WGS identified genetic causes in 26/114 (23%). Including all initial 124 families, the combined diagnostic yield was 36/124 (29%), with three diagnoses from SNP-array, seven 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 kidney failure was the only predictor of positive genetic screening; however, 18/99 (18%) of patients without such family history still had a genetic kidney disease. Additionally, we propose biallelic variants in complex I assembly factor gene TMEM126B as a cause of adult-onset kidney disease. Conclusion WGS identified a genetic cause in 23% of patients with uKF ≤50 years, resulting in a combined diagnostic rate of 29%. Most pathogenic variants were detectable by WGS.