Congenital Abnormalities of the Kidney and Urinary Tract (CAKUT) Panel

Congenital anomalies of kidney and urinary tract (CAKUT) represent a wide spectrum of structural malformations of the kidney and/or urinary tract due to defects during embryonic kidney development, accounting for 40-50% of children with chronic kidney disease worldwide (Sanna-Cherchi et al. 2018. PubMed ID: 29293093; Vivante et al. 2014. PubMed ID: 24398540; Nicolaou et al. 2015. PubMed ID: 26281895). The most common malformation is ureteropelvic junction obstruction (~20%). Other common clinical features within the CAKUT spectrum include renal agenesis, renal hypodysplasia, multicystic dysplastic kidney, hydronephrosis, megaureter, ureter duplex, vesicoureteral reflux (VUR), and posterior urethral valves. Age of onset of CAKUT varies from in utero to adulthood.

CAKUT is a group of highly genetically and phenotypically heterogeneous diseases resulting from disturbances in normal nephrogenesis due to exposure to environmental risk factors or/and genetic defects (Sanna-Cherchi et al. 2018. PubMed ID: 29293093; Vivante et al. 2014. PubMed ID: 24398540; Nicolaou et al. 2015. PubMed ID: 26281895). Genetic diagnosis of CAKUT has been challenging due to genetic and phenotypic heterogeneity as well as incomplete genetic penetrance. Although studies suggest that the pathogenesis of the CAKUT spectrum is multifactorial (influenced by genetics, epigenetic and environmental factors), dozens of genes to date have been found to cause monogenic CAKUT; and copy number variations (CNVs) have been widely associated with CAKUT spectrum (Sanna-Cherchi et al. 2018. PubMed ID: 29293093). The implicated genes encode proteins in diverse developmental pathways. Inheritance modes of monogenic CAKUT include autosomal recessive (AR), autosomal dominant (AD) and X-linked (XL). The spectrum of pathogenic variants in causative genes includes all types of variants.

Overall, rare CNVs or single-nucleotide variants (SNVs) collectively explain at most 20% to 25% of CAKUT cases. Rates tend to be higher in patients with renal agenesis or hypodysplasia (RHD) (Sanna-Cherchi et al. 2018. PubMed ID: 29293093).

To date, HNF1B and PAX2 are the most frequent CAKUT-causing genes, accounting for about 5–15% of cases depending on the examined cohort (Vivante et al. 2014. PubMed ID: 24398540).

In a study of 62 families with CAKUT, pathogenic single-nucleotide variants (SNVs) in PAX2, HNF1B, and EYA1 were identified approximately 5% of families (Bekheirnia et al. 2017. PubMed ID: 27657687).

In a study of a total of 677 CAKUT patients and 301 patients with VACTERL association, Saisawat et al. identified TRAP1 recessive pathogenic variants in about 0.5% of the patients (Saisawat et al. 2014. PubMed ID: 24152966).

In a group of 311 patients with CAKUT, 7 (2.3%) were found to have heterozygous DSTYK pathogenic variants (Sanna-Cherchi et al. 2013. PubMed ID: 23862974).

Next generation sequencing panel testing for patients with CAKUT demonstrated that <10% patients with isolated CAKUT carry variants in genes such as HNF1B, PAX2, EYA1, SIX5, and RET (Nicolaou et al. 2015. PubMed ID: 26281895).

In 5 out of 590 families (2.5%) affected by isolated CAKUT, recessive pathogenic variants were identified in the Fraser syndrome-related genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1 (Kohl et al. 2014. PubMed ID: 24700879).

In a study of 183 unrelated families affected by CAKUT, 16 (8.7%) heterozygous pathogenic or suspected pathogenic variants in GREB1L were identified, 12 of which were found in 54 cases (25.8%) with bilateral kidney agenesis in this cohort (De Tomasi et al. 2017. PubMed ID: 29100091). In another study of 612 individuals affected by renal agenesis and hypodysplasia (RHD), 17 (2.8%) heterozygous pathogenic or suspected pathogenic variants in GREB1L were identified (Sanna-Cherchi et al. 2017. PubMed ID: 29100090).

For many genes of this panel, due to high genetic and phenotypic heterogeneity, pathogenic variant detection rate of each individual gene in a larger cohort of patients with CAKUT relevant phenotypes is unavailable.

At this time, the clinical sensitivity of deletion/duplication testing is difficult to estimate due to the lack of large cohort studies. However, copy number variations of large size (beyond a gene-centric scale) have been indicated to be a common cause of the CAKUT spectrum. For example, in a study involving 522 patients with CAKUT, 72 distinct known or novel copy-number variations in 87 (16.6 %) patients were identified (Sanna-Cherchi et al. 2012. PubMed ID: 23159250).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.7% 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).

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). Our current sequencing methodology has not been validated to detect this variant.

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).