Emerging Role of Clinical Genetics in CKD

Abstract

Chronic kidney disease (CKD) afflicts 15% of adults in the United States, of whom 25% have a family history. Genetic testing is supportive in identifying and possibly confirming diagnoses of CKD, thereby guiding care. Advances in the clinical genetic evaluation include next-generation sequencing with targeted gene panels, whole exome sequencing, and whole genome sequencing. These platforms provide DNA sequence reads with excellent coverage throughout the genome and have identified novel genetic causes of CKD. New pathologic genetic variants identified in previously unrecognized biological pathways have elucidated disease mechanisms underlying CKD etiologies, potentially establishing prognosis and guiding treatment selection. Molecular diagnoses using genetic sequencing can detect rare, potentially treatable mutations, avoid misdiagnoses, guide selection of optimal therapy, and decrease the risk of unnecessary and potentially harmful interventions. Genetic testing has been widely adopted in pediatric nephrology; however, it is less frequently used to date in adult nephrology. Extension of clinical genetic approaches to adult patients may achieve similar benefits in diagnostic refinement and treatment selection. This review aimed to identify clinical CKD phenotypes that may benefit the most from genetic testing, outline the commonly available platforms, and provide examples of successful deployment of these approaches in CKD.

Keywords: Chronic kidney disease; clinical genetics; genetic causes; genetic disorders; genetic testing; next-generation sequencing.

Figure 1

Indications for genetic testing in CKD. Clinical genetics should be considered in CKD if the etiology is unclear, when a genetic component is clinically suspected (positive family history, early onset, extrarenal manifestations, unusual disease course), or to guide therapy (eg, immunosuppression management, pretransplant evaluation). Abbreviation: CKD, chronic kidney disease.

Figure 2

Different approaches to genetic testing. Sanger sequencing is limited to a narrow portion of the genome. In targeted gene panels, only coding portions of a specific set of genes are targeted. Whole exome sequencing captures almost all coding sequences, and whole genome sequencing covers nearly all regions of the genome.