Screening for genetic kidney diseases in a dialysis cohort via exome sequencing

Abstract Background Monogenic causes are increasingly recognized in end-stage kidney disease (ESKD), but the real-world diagnostic efficacy of exome sequencing in unselected dialysis cohorts is still being defined. Methods We conducted a prospective study enrolling 317 adult ESKD patients from a single center in Taiyuan, China, regardless of presumed etiologyWhole-exome sequencing (WES) was performed on peripheral blood DNAVariants were curated and classified per the ACMG/AMP 2015 and ACGS guidelines, with only ‘pathogenic’ or ‘likely pathogenic’ findings considered diagnostic. Results The cohort was 59% male, mean ESKD onset 53.2 ± 14.3 yearsA definitive monogenic diagnosis emerged in 7.3% (23/317) of patients, in line with multicenter and international studiesGenes most frequently implicated were PKD1 (3.5% of cohort; 47.8% of genetically diagnosed) and COL4A3/4/5 (1.9%; 26.1% of diagnosed), reflecting global trends of autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome as major genetic contributors in adult ESKDNotably, mutations in ACTN4, PAX2, COQ8B or INF2, causing hereditary steroid-resistant nephrotic syndrome (SRNS), led to significantly earlier ESKD onset (mean 31.3 years) compared to PKD1 or COL4-related casesInconclusive genetic findings were present in 7.9% (25/317)Most patients reported no family history of kidney disease, indicating the limitations of clinical suspicion alone. Conclusions In a real-world Chinese dialysis cohort, WES provided a molecular diagnosis in 7.3% of cases, demonstrating clinical utility for risk stratification, family counseling, donor selection, and actionable therapyThese findings underscore the need for routine integration of genetic testing in ESKD care irrespective of family history, especially to clarify ambiguous cases and optimize management.