Whole genome sequencing for CKD of unexplained cause in Hong Kong

A significant proportion of patients present with chronic kidney disease of unexplained cause (CKDx) despite standard-of-care diagnostic workup. Data from Australian, European and United States cohorts show that some are due to monogenic etiology. The diagnostic yield and clinical utility of genetic testing in Chinese patients remains unclear.

We prospectively recruited adult CKDx patients following up at Queen Mary Hospital nephrology unit from 1 Oct 2022 to 1 June 2024. After genetic counselling, patients underwent whole genome sequencing focused on kidney disease genes(637 genes). Variants classification was performed according to the American College of Medical Genetics guidelines.

Among 131 CKDx patients, 92% self-identified as Chinese and 21% presented with kidney failure. Mean age at clinical presentation was 35 years. 36% had positive family history of CKD. We identified Pathogenic/Likely pathogenic variants in 13 patients, giving a diagnostic yield of 10%. 33% of variants identified were novel. Variants in type IV collagen genes(COL4A3, COL4A5, COL4A4) were the most frequent, followed by ALG9, CEP290 and IFT140. Alport-spectrum disorders were the leading genetic diagnoses, representing 77% of all genetically positive cases. A significantly higher proportion of patients with positive genetic findings had positive family history of CKD or CKDx, compared to those with negative genetic findings (CKD: 85% versus 31%, p<0.001; CKDx: 77% versus 19%, p<0.001).

Monogenic etiology could be established in 10% of adult CKDx patients in Hong Kong. Alport-spectrum disorders were the leading genetic diagnoses, followed by atypical Autosomal Dominant Polycystic Kidney Disease and nephronophthisis. Genetic testing in CKDx population is clinically useful since a significant proportion could reach a diagnosis and permit disease specific management.