Broad Gene Panel Diagnoses Patients With Kidney Disease

Identification of monogenic causes of CKD, which are present in ∼10% of adult cases, can impact prognosis and patient management. For the ∼800,000 individuals in the USA with end-stage kidney disease (ESKD), genetic diagnosis may inform the selection of potential-related kidney donors, assess the risk of disease recurrence, and guide clinical management following transplant.

Broad gene panels offer several advantages over mutational analysis of individual genes or targeted panels. The phenotypic variability of rare and multisystem disorders, including the unpredictable interaction of causative variants, complicates the selection of appropriate targets. Broad gene panels provide an economical, comprehensive analysis that can reduce barriers to testing by streamlining testing procedures, reimbursement, report structure, and genetic counseling capabilities.

A team of Nephrologists led by those at Wake Forest School of Medicine (Winston-Salem, NC, USA) carried out a retrospective analysis of 1,007 consecutive tests performed on patients with a 382 renal gene NGS panel (the Renasight test, Natera, San Carlos, CA, USA). The median age was 46 years (range 5–91), of which, 52.7% (531/1,007) were female. Information about a patient’s kidney disease status was available for 96.5% (973/1,007) of cases, of which 95.0% (924/973) were affected.

Genomic DNA isolated from the accessioned samples (blood or buccal saliva) was prepared into libraries using a customized hybrid capture enrichment protocol targeting key coding exons and splicing junctions based on IDT xGen Lockdown probe chemistry (Integrated DNA Technologies, Inc., Coralville, IA, USA). Paired-end sequencing was then performed on DNA libraries on the Illumina platform 2,500 HiSeq or NovaSeq 6,000 (Illumina, San Diego, CA, USA), using 300bp reads.

The scientists reported pathogenic (P) and likely pathogenic (LP) variants. Positive findings included a monoallelic P/LP variant in an autosomal dominant or X-linked gene and biallelic P/LP variants in autosomal recessive genes. Positive genetic findings were identified in 21.1% (212/1,007) of cases. A total of 220 positive results were identified across 48 genes. Positive results occurred most frequently in the PKD1 (34.1%), COL4A5 (10.9%), PKD2 (10.0%), COL4A4 (6.4%), COL4A3 (5.9%), and TTR (4.1%) genes. Variants identified in the remaining 42 genes comprised 28.6% of the total positive findings, including single positive results in 26 genes. Positive results in >1 gene were identified in 7.5% (16/212) of cases.

The authors concluded that genetic results from individuals tested with the Renasight test, a broad gene panel for evaluation for CKD, nephrolithiasis, and electrolyte abnormalities, revealed a high rate of positive findings representing a variety of both common, and rare genetic diagnoses. The study revealed cases in which positive findings were identified in more than one gene. The study was published on March 24, 2022 in the American Journal of Nephrology.

Related Links:
Wake Forest School of Medicine 
Natera 
Integrated DNA Technologies 
Illumina