PGmax^TM - Comprehensive Inherited Kidney Diseases Panel

Inherited kidney diseases encompass a clinically and genetically heterogeneous group of progressive conditions due to pathogenic variants in single genes that disturb renal growth, structure, and function (Devuyst et al. 2014. PubMed ID: 24856029; Hildebrandt. 2010. PubMed ID: 20382325). In addition to pediatric patients, inherited kidney diseases also have a high prevalence in adults, accounting for up to 37% of adults with renal diseases (Cocchi et al. 2020. PubMed ID: 32646915; Connaughton et al. 2019. PubMed ID: 30773290; Lata et al. 2018. PubMed ID: 29204651). With an overall prevalence of approximately 6-8 in 10,000 births in the USA and Europe, more than 160 different inherited kidney diseases have been identified to date. Among individuals who progress to renal-replacement therapy, nearly all children and at least 10% of adults are affected by an inherited kidney disease (Devuyst et al. 2014. PubMed ID: 24856029). Based on nephron segments and the function of the involved genes, these kidney diseases can be primarily classified into the following categories: congenital anomalies of the kidney and urinary tract (CAKUT), ciliopathies and tubulointerstitial diseases, glomerular diseases, renal tubular diseases and metabolic diseases, and nephrolithiasis. Inherited kidney disorders can have complications in other organs such as the eyes, liver, brain, bone, and skin. In addition, this panel also includes syndromic disorders that have renal involvement such as von Hippel-Lindau syndrome and Alagille syndrome.

Genetic testing for inherited kidney diseases in both pediatric and adult populations is critical for confirmation of clinical diagnosis, differential diagnosis, and personalized management and treatment; genetic testing has therefore been increasingly integrated into clinical practice (Lemaire and Parekh. 2017. PubMed ID: 29146703; Cocchi et al. 2020. PubMed ID: 32646915). 

Inherited kidney diseases are clinically and genetically heterogeneous and may be transmitted in an autosomal dominant (including de novo), autosomal recessive or X-linked manner. Causative variants include missense, nonsense, frameshift, splicing, regulatory, and copy number alterations.

Inherited kidney diseases are caused by defects in genes encoding a broad range of proteins including channels, transporters, receptors, enzymes, transcription factors, and structural components. These proteins can also play an important role in extrarenal organs such as the eyes, liver, brain, bone, and skin (Devuyst et al. 2014. PubMed ID: 24856029).

This large panel essentially includes all the tests for inherited kidney diseases available in PreventionGenetics. See individual gene summaries for information on molecular biology of gene products and spectra of pathogenic variants.

To our knowledge, no overall clinical sensitivity has been reported in the literature for comprehensive inherited kidney diseases with testing greater than 300 genes. Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this large panel is difficult to estimate and varies largely depending on phenotypes and the underlying etiology.

However, based on the subgroups of inherited kidney diseases mentioned in the clinical features section, sensitivity data is available for the majority of subpanels. Please see our individual subpanels for more information about clinical sensitivity. Cocchi et al. reviewed the literature and summarized diagnostic yield of inherited kidney diseases by phenotype and genetic test type (Cocchi et al. 2020. PubMed ID: 32646915).

This test is performed using next-generation sequencing (NGS) with additional Sanger sequencing as necessary.

This panel typically provides 99.0% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies (i.e. paralogous sequence) in the genome (including the following regions: ALG exon 12, NOTCH2 exons 1-4 and TNXB exons 32-44). Therefore, a small fraction of sequence variants relevant to the patient's health may not be detected. For the APOL1 gene, we only test the risk alleles G1 and G2.   

To date, the only documented pathogenic variant in MUC1 causing medullary cystic kidney disease is the insertion of a single cytosine in one copy of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence (Kirby et al. 2013. PubMed ID: 23396133). Our current sequencing methodology has not been validated to detect this variant.

The report will not include all the observed rare variants due to the large number of genes included in this panel. Pathogenic, likely pathogenic, uncertain and risk variants that are considered to contribute to the patient's phenotype will be reported. A list of all rare variants included in this panel is available along with our interpretations upon request.

Reports will consist of two different sections:

• Variants in genes known to be associated with the provided phenotype
• Variants in genes possibly associated with the provided phenotype

Exome-wide CNV analysis is included at no additional charge as part of this test.  In addition to phenotypically-relevant CNVs, we will also report any rare deletions ≥ 250 kb in size and rare duplications ≥ 500 kb in size. In rare cases, sequence paralogy (e.g., pseudogenes, segmental duplications), sequence properties, deletion/duplication size, and inadequate coverage may impact our ability to identify and/or interpret a CNV. 

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).