NephroCheck+

Genetic testing for nephrology

Our panels consist of 98 genes chosen through a careful process that involves reviewing gene reviews, variant databases (HGMD and ClinVar), recent literature, and customer feedback. With our panels, you’ll get improved clinical usefulness, maximum diagnostic yield, more accurate differential diagnosis, and access to the latest analytically validated genes. We also highly cover difficult-to-sequence genes, ensuring that our panels have a real diagnostic impact, even in challenging cases.

Inherited renal diseases are estimated to cause 50% of pediatric chronic renal failure (CRF) and 20% of adult CRF. Many kidney disorders lead to end-stage renal disease (ESRD) – permanent loss of the kidneys that requires a kidney transplant. Many patients with nephrotic syndrome (NS) suffer from so-called steroid-resistant NS. For these patients, the prognosis is poor, as 30–40% develop ESRD requiring dialysis and transplantation.

Discover how genetic diagnostics can benefit patients with kidney-related illnesses.

Genetic causes of kidney diseases include several single-gene disorders, a variety of chromosomal abnormalities, and many multifactorial disorders. A genetic cause may be suspected from known family history or the simultaneous occurrence of other medical problems, but in many cases, disease presentation is unexpected.

It is crucial to obtain an accurate genetic diagnosis to ensure proper treatment and screening for related conditions. Identifying the specific congenital disability and inheritance pattern can also aid in testing family members at risk.

For individuals with NS, genetic testing can prevent the need for ineffective treatment with steroids and other immunosuppressive medications. Identifying the specific mutations causing the disease can also aid in predicting the likelihood of recurrence after a transplant. Patients with a genetic cause of NS typically have a lower recurrence risk than those without a genetic cause.

Test Methodology

The Comprehensive Nephrology Panel is designed to detect single nucleotide variants (SNVs) and small insertions and deletions in 63genes associated with neurological risk. Targeted regions for this panel include the coding exons and 10 bp intronic sequencesimmediate to the exon-intron boundary of each coding exon in each of these genes. Extracted patient DNA is prepared using targetedhybrid capture, assignment of a unique index, and sequencing via Illumina sequencing by synthesis (SBS) technology. Data is alignedusing human genome build GRCh37. Variant interpretation is performed according to current American College of Medical Geneticsand Genomics (ACMG) professional guidelines for the interpretation of germline sequence variants using Fabric EnterpriseTM Pipeline6.6.15. Variant interpretation and reporting is performed by Fabric Clinical (CLIA ID: 45D2281059 and CAP ID: 9619501). The followingquality filters are applied to all variants: quality <500, allelic balance <0.3, coverage <10x.

Genes Evaluated

ACTN4, AHI1, AVP, AVPR2, BBS1, BBS10, BBS2, BCS1L, BOLA3, C10orf2, CASR, CEP290, CFTR, CLCNKB, COL4A1, COL4A3, COL4A5, DGUOK, DHCR7, DNM1L, ECHS1, EGF, EYA1, FAH, FBXL4, FGF23, FOXRED1, HNF1B, HNF4A, HSD11B2, INF2, JAG1, KCNJ1, KCNJ10, LAMB2, LEPR, LRP5, MC4R, MPV17, MT-ATP6, MT-CO1, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, MT-RNR1, MT-TC, MT-TE, MT-TF, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-TQ, MT-TR, MT-TS1, MT-TS2, MT-TV, MT-TW, MT-TY, NDUFAF2, NDUFS1, NFU1, NPHP1, NPHS1, NPHS2, NTRK2, OPA1, PAX2, PHEX, PKD1, PKD2, PKHD1, PLCE1, POLG, POLG2, RRM2B, SCNN1A, SCNN1B, SCNN1G, SLC12A1, SLC12A3, SLC25A4, SUCLA2, SUCLG1, TK2, TMEM67, TMEM70, TRPC6, TSC1, TSC2, TYMP, UMOD, VHL, VPS13B, WT1

Test Limitations

This test aims to detect all clinically relevant variants within the coding regions of the genes evaluated. Pathogenic and likelypathogenic variants detected in these genes should be confirmed by orthogonal methods. Detected genetic variants classified asbenign, likely benign, or of uncertain significance are not included in this report. Homopolymer regions and regions outside of thecoding regions cannot be captured by the standard NGS target enrichment protocols. At this time, the assay does not detect largedeletions and duplications. This analysis also cannot detect pathogenic variants within regions which were not analyzed (e.g., introns,promoter and enhancer regions, long repeat regions, and mitochondrial sequence). This assay is not designed to detect mosaicismand is not designed to detect complex gene rearrangements or genomic aneuploidy events. It is important to understand that theremay be variants in these genes undetectable using current technology. Additionally, there may be genes associated with neurologicalpathology whose clinical association has not yet been definitively established. The test may therefore not detect all variantsassociated with neurological pathology. The interpretation of variants is based on our current understanding of the genes in this paneland is based on current ACMG professional guidelines for the interpretation of germline sequence variants. Interpretations maychange over time as more information about the genes in this panel becomes available. Qualified health care providers should beaware that future reclassifications of genetic variants can occur as ACMG guidelines are updated. Factors influencing the quantityand quality of extracted DNA include, but are not limited to, collection technique, the amount of buccal epithelial cells obtained, thepatient’s oral hygiene, and the presence of dietary or microbial sources of nucleic acids and nucleases, as well as other interferingsubstances and matrix-dependent influences. PCR inhibitors, extraneous DNA, and nucleic acid degrading enzymes may adversely affect assay results.

Regulatory Disclosures

This laboratory developed test (LDT) was developed and its performance characteristics were determined by PreCheck HealthServices, Inc. This test was performed at PreCheck Health Services, Inc. (CLIA ID: 10D2210020 and CAP ID: 9101993) that is certifiedunder the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high complexity testing. This assayhas not been cleared or approved by the U.S. Food and Drug Administration (FDA). Clearance or approval by the FDA is not requiredfor the clinical use of this analytically and clinically validated laboratory developed test. This assay has been developed for clinicalpurposes and it should not be regarded as investigational or for research.

References

1. Zhang MQ. Human molecular genetics. 1998, May. Statistical features of human exons and their flanking regions. (PMID: 9536098)

2. Baralle D, Baralle M. Journal of medical genetics. 2005, Oct. Splicing in action: assessing disease causing sequence changes. (PMID:16199547)

3. Cízková A, Stránecký V, Mayr JA, Tesarová M, et al. Nature genetics. 2008, Nov. TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. (PMID: 18953340)

4. Spiegel R, Khayat M, Shalev SA, Horovitz Y, et al. Journal of medical genetics. 2011, Mar. TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome. (PMID: 21147908)

5. Catteruccia M, Verrigni D, Martinelli D, Torraco A, et al. Molecular genetics and metabolism. 2014, Mar. Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients. (PMID: 24485043)

6. Braczynski AK, Vlaho S, Müller K, Wittig I, et al. BioMed research international. 2015. ATP synthase deficiency due to TMEM70 mutation leads to ultrastructural mitochondrial degeneration and is amenable to treatment. (PMID: 26550569)

^{All NGS panels have a turnaround time of 10-14 days for results.}

^{Each panel is designed to detect single nucleotide variants (SNVs) and small insertions and deletions with gene specific limitations.Targeted regions include the coding exons and 10 bp intronic sequences immediate to the exon-intron boundary of each coding exonin each of these genes.}