Nephrology

Genetic testing is clinically relevant for the following indications, including but not limited to:

• Persistent haematuria of unknown origin, with or without proteinuria or sensorineural hearing loss
• Unexplained or steroid-resistant nephrotic syndrome
• Cystic kidney disease requiring diagnostic confirmation, prognostic refinement, or reproductive risk assessment
• Progressive CKD with non-diagnostic urinalysis in the setting of a positive family history
• Congenital renal anomalies () identified antenatally or postnatally, particularly when syndromic features are suspected
• Unexplained hypokalemic metabolic alkalosis with renal salt wasting
• Infant-onset metabolic acidosis, nephrocalcinosis, or unexplained sensorineural hearing loss
• Early-onset nephrolithiasis or nephrocalcinosis, hypercalciuria, or associated paediatric growth failure

Molecular testing provides the highest yield when clinical features suggest an inherited kidney disease, but first-line investigations fail to establish a definitive diagnosis. Identifying a pathogenic germline variant establishes a precise molecular diagnosis, guides targeted clinical management, and informs genetic counseling. In patients with , distinguishing genetic aetiologies from primary or secondary forms prevents unnecessary exposure to toxic immunosuppressive therapies, informs renal transplantation prognosis, and guides living-related donor evaluation.

Variants are classified according to joint American College of Medical Genetics and Genomics and Association for Molecular Pathology () guidelines:

• Pathogenic / likely pathogenic: Confirms a molecular diagnosis matching the patient’s clinical phenotype.
• Variant of uncertain significance (VUS): Inconclusive result due to insufficient evidence to establish or rule out pathogenicity. Periodic re-evaluation of VUS findings is recommended as population and functional data evolve.
• No pathogenic variant detected: Does not completely exclude a genetic aetiology. Causative variants may reside in non-coding or regulatory regions, involve complex structural rearrangements, affect genes not yet linked to disease, or exist within genomic regions inaccessible to short-read sequencing.

Identification of a germline variant dictates disease-specific surveillance and targeted interventions aligned with consensus guidelines. Confirmed genetic findings carry implications for at-risk relatives, enabling cascade testing.

Formal is recommended both pre- and post-test. Pre-test counseling establishes patient clinical history, addresses methodology limitations, and sets expectations. Post-test counseling supports the interpretation of complex findings (including VUS), addresses recurrence risks, and guides family management.

Testing uses based exome sequencing and virtual multi-gene panels to detect sequence changes. Copy-number analysis is performed using NGS data.

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