ABSTRACT
BACKGROUND: The cause of kidney failure is unknown in approximately 10% of patients with stage 5 chronic kidney disease (CKD). For those who first present to nephrology care with kidney failure, standard investigations of serology, imaging, urinalysis and kidney biopsy are limited differentiators of etiology. We aimed to determine the diagnostic utility of whole-genome sequencing (WGS) with analysis of a broad kidney gene panel in patients with kidney failure of unknown cause. METHODS: We prospectively recruited 100 participants who reached CKD stage 5 at 50 years of age and had an unknown cause of kidney failure after standard investigation. Clinically-accredited WGS was performed in this national cohort after genetic counselling. The primary analysis was targeted to 388 kidney-related genes with second-tier genome-wide and mitochondrial analysis. RESULTS: The cohort was 61% male and the average age of participants at stage 5 CKD was 32 years (9 months to 50 years). A genetic diagnosis was made in 25% of participants. Disease-causing variants were identified across autosomal dominant tubulointerstitial kidney disease (6), glomerular disorders (4), ciliopathies (3), tubular disorders (2), Alport syndrome (4) and mitochondrial disease (1). Most diagnoses (80%) were in autosomal dominant, X-linked or mitochondrial conditions (UMOD; COL4A5; INF2; CLCN5; TRPC6; COL4A4; EYA1; HNF1B; WT1; NBEA; m.3243A>G). Patients with a family history of CKD were more likely to have a positive result (OR 3.29, 95% CI 1.10-11.29). Thirteen percent of participants without a CKD family history had a positive result. In those who first presented in stage 5 CKD, WGS with broad analysis of a curated kidney-disease gene panel was diagnostically more informative than kidney biopsy, with biopsy being inconclusive in 24 of 25 participants. CONCLUSIONS: In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.
ABSTRACT
Background: Newborn bloodspot screening (NBS) programs have improved neonatal healthcare since the 1960s. Genomic sequencing now offers potential to generate polygenic risk score (PRS) that could be incorporated into NBS programs, shifting the focus from treatment to prevention of future noncommunicable disease (NCD). However, Australian parents' knowledge and attitudes regarding PRS for NBS is currently unknown. Methods: Parents with at least one Australian-born child under 18 years were invited via social media platforms to complete an online questionnaire aimed at examining parents' knowledge of NCDs, PRS, and precision medicine, their opinions on receiving PRS for their child, and considerations of early-intervention strategies to prevent the onset of disease. Results: Of 126 participants, 90.5% had heard the term "non-communicable disease or chronic condition," but only 31.8% and 34.4% were aware of the terms "polygenic risk score" and "precision medicine" respectively. A large proportion of participants said they would consider screening their newborn to receive a PRS for allergies (77.9%), asthma (81.0%), cancer (64.8%), cardiovascular disease (65.7%), mental illness (56.7%), obesity (49.5%), and type 2 diabetes (66.7%). Additionally, participants would primarily consider diet and exercise as interventions for specific NCDs. Discussion: The results from this study will inform future policy for genomic NBS, including expected rate of uptake and interventions that parents would consider employing to prevent the onset of disease.
