Clinical Genetic Screening in Adult Patients with Kidney Disease

Abstract

Expanded accessibility of genetic sequencing technologies, such as chromosomal microarray and massively parallel sequencing approaches, is changing the management of hereditary kidney diseases. Genetic causes account for a substantial proportion of pediatric kidney disease cases, and with increased utilization of diagnostic genetic testing in nephrology, they are now also detected at appreciable frequencies in adult populations. Establishing a molecular diagnosis can have many potential benefits for patient care, such as guiding treatment, familial testing, and providing deeper insights on the molecular pathogenesis of kidney diseases. Today, with wider clinical use of genetic testing as part of the diagnostic evaluation, nephrologists have the challenging task of selecting the most suitable genetic test for each patient, and then applying the results into the appropriate clinical contexts. This review is intended to familiarize nephrologists with the various technical, logistical, and ethical considerations accompanying the increasing utilization of genetic testing in nephrology care.

Keywords: CGH array; Chronic; Genetic Testing; High-Throughput Nucleotide Sequencing; Kidney Genomics Series; Patient Care; Renal Insufficiency; Sanger sequencing; array techniques; chronic kidney disease; familial kidney disease; familial nephropathy; genetic renal disease; genetics; genomics; human genetic testing; human genetics; kidney disease; massive parallel sequencing; medical genetics; microarray techniques; nephrology; referral and consultation; translations; whole exome sequencing; whole genome sequencing.

Figure 1.

Genetic testing options. Different classes of variants identifiable in human genome and how they are detected by the currently available genetic tests. The top part shows a “large-scale” section where an entire chromosome is represented (blue), as well as the relative large alterations (aka structural variants); chromosomal rearrangement (deletions, duplications, inversions, and translocations caused by a breakage in the DNA at two different locations, followed by a rejoining of the broken ends to produce a new chromosomal arrangement of genes); chromosomal imbalance (absence or duplication of a chromosomal portion) identifiable primarily through chromosomal array–based techniques; and copy number variation (a duplication or deletion that affects a large stretch of sequence, at least 1 kb). Small variants: single nucleotide variants (SNVs; substitution of a single base) and small insertion/deletions (INDELs; involving more than one base). We also see the coding (green), noncoding (dark gray), and regulatory (noncoding) portions of the genome that constitute each gene (gene A, gene B, and gene C) and how these are sequenced and analyzed through different techniques. Sanger sequencing is limited to a narrow portion of the genome, usually a single gene or small regions of a gene. Targeted gene panels: only coding portions of a specific set of genes are targeted. Exome sequencing captures nearly all of the coding sequences in an individual’s genome. Genome sequencing covers nearly all regions of the genome (coding and noncoding regions) of an individual.

Figure 2.

Clinical determinants of genetic risk and their influence on genetic test type. The figure summarizes the clinical characteristics shaping the pretest risk of a genetic disease in a nephrology patient. Young age at onset, family history of kidney disease, and presence of extrarenal features are all predictive of genetic disease. Moreover, depending on the clinical diagnosis, the diagnostic yield of genetic testing varies. The yields of different modalities is shown in Figure 3. CAKUT, congenital anomalies of kidney and urinary tract; SRNS, steroid-resistant nephrotic syndrome; uCKD, CKD of unknown etiology.

Figure 3.

Diagnostic yield per phenotype and genetic test type. The figure represents the diagnostic yield in different phenotype cohorts obtained through different genetic test type in pediatric and adult genetic studies on kidney disease. The y axis represents the percentage of diagnostic rate for the cohort (specified above each bar with the relative citation). The x axis represents the study under consideration; the width of the bar is dependent on the sample size for each study. The familial yellow flag indicates whether the study considered families (not individuals). The colored legend below the plot indicates the genetic test utilized in the study cohort. mA, chromosomal microarray techniques (especially in CAKUT); TGP, targeted gene panel; WES, whole exome sequencing; WGS, whole genome sequencing. The studies depicted here are presented in the Supplemental Material.

Box 1.

Establishing a genetic diagnosis can support personalized nephrology care: A case study.