Expanding opportunities and emerging challenges: broadening the scope of genetic testing in nephrology

Abstract

Massively parallel sequencing technologies such as exome sequencing are increasingly applied across medicine. Connaughton et al. report a high diagnostic yield of exome sequencing among adults with hereditary nephropathy or nephropathy of unknown cause. Their findings support broader use of genomic sequencing in nephrology and highlight key associated questions, including how to identify those patients for whom testing is indicated, pinpoint pathogenic variants, and balance the resultant health care benefits and clinical follow-up burden.

Figure 1 |. Massively parallel sequencing (MPS) in nephrology: current practices, potential future usage, and associated questions.

The key aspects of MPS in nephrology include (i) patient populations assessed and determination of the first-line genetic testing modality; (ii) genetic analysis procedures; and (iii) clinical application of the genetic findings detected. (a) Current use of MPS consists largely of applying disease-targeted multigene panels as a first-line test to probands clinically diagnosed with the associated disease. If the clinical impression is uncertain or the presentation wholly nondiagnostic, sequential gene panel testing or exome sequencing (ES) or genome sequencing (GS) may be applied instead. Genetic analysis assesses rare variants occurring in the genes included on the panel; for ES or GS, rare variants in known Mendelian nephropathy-associated genes are assessed. Return of results and follow-up clinical care are generally conducted as part of the patient’s routine nephrologic care, with his or her existing nephrologist. (b) Potential future use of MPS involves applying genome-wide testing (exome sequencing or genome sequencing) to a broader population, which may include individuals not known to have chronic kidney disease (CKD; e.g., for purposes of disease screening and presymptomatic genetic diagnosis, or, among probands undergoing genomic sequencing for other disease indications, as secondary genetic findings) as well as patients with CKD of diverse etiologies, including those presumed to have acquired causes of disease (e.g., diabetic nephropathy). The scope of genetic analysis may expand to all genes (genome-wide), integrating genetic diagnostics with case-control analyses for novel gene discovery. As the disorders detected often involve multiple organ systems, and the patients sequenced may not have previously been under nephrologic care, return of results and clinical follow-up will involve a multidisciplinary team, including other medical subspecialists for the organ systems affected by the given disease, and genetic counselors. (c) The key questions associated with this expanded, future use include (i) the clinical indications for genetic workup for Mendelian forms of CKD, (ii) determining which genes should be assessed and which filtering parameters most effectively identify bonafide disease-causal variants in the context of the abundance of putatively damaging variation present in any human genome, and (iii) determining which health care professionals should be involved and how to balance the opportunity to identify potentially medically actionable conditions with the financial and psychosocial burdens of the often considerable clinical follow-up.