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

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.

We conducted a prospective study enrolling 317 adult ESKD patients from a single center in Taiyuan, China, regardless of presumed etiology. Whole-exome sequencing (WES) was performed on peripheral blood DNA. Variants were curated and classified per the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 2015 and Association for Clinical Genomic Science (ACGS) guidelines, with only "pathogenic" or "likely pathogenic" findings considered diagnostic.

The cohort was 59% male, mean ESKD onset 53.2 ± 14.3 years. A definitive monogenic diagnosis emerged in 7.3% (23/317) of patients, in line with multicenter and international studies. Genes 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 and Alport syndrome as major genetic contributors in adult ESKD. Notably, mutations in ACTN4, PAX2, COQ8B or INF2, causing hereditary steroid-resistant nephrotic syndrome, led to significantly earlier ESKD onset (mean 31.3 years) compared with PKD1 or COL4-related cases. Inconclusive 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.

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 therapy. These 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.