Atypical Hemolytic-Uremic Syndrome and Nephrotic Syndrome via the DGKE Gene

Hemolytic-uremic syndrome (HUS) is characterized by episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical hemolytic-uremic syndrome (aHUS) is characterized by glomerular microangiopathy, non-immune hemolytic anemia and thrombocytopenia (Nester et al. 2015). Compared with the more common diarrhea-associated HUS (D+HUS), aHUS has a much higher risk of progression to end-stage renal failure (50%) or death (25%). Patients with DGKE-related aHUS develop symptoms in the first year of life including persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and progressive chronic kidney disease (Lemaire et al. 2013; Quaggin 2013; Westland et al. 2014). This is a type of aHUS not related to abnormal activation of the complement system.

DGKE defects can also cause nephrotic syndrome in early childhood, mostly in the first five years of life, with proteinuria and low serum albumin at onset (Ozaltin et al. 2013). The remarkable feature of renal biopsies in DGKE-caused nephrotic syndrome is glomerular injury with membranoproliferative glomerulonephritis (MPGN). Progression rate to end-stage renal failure varies among these patients.

Both DGKE-related aHUS and nephrotic syndrome are autosomal recessive disorders (Lemaire et al. 2013; Westland et al. 2014; Ozaltin et al. 2013). The DGKE gene has 11 coding exons that encode diacylglycerol kinase-epsilon, an intracellular lipid kinase that phosphorylates diacylglycerol (DAG) to phosphatidic acid. Genetic defects of DGKE found to date include missense, nonsense, splicing mutations and small deletions (Human Gene Mutation Database). No large deletions or duplications have been reported.

Among 83 unrelated probands with early-onset atypical hemolytic uremic syndrome (DGKE pathogenic variants were found in four (6.8%) (Sánchez Chinchilla et al. 2014).

Among 142 unrelated probands with membranoproliferative glomerulonephritis (MPGN), DGKE pathogenic variants were found in two (1.4%) (Ozaltin et al. 2013).

This test provides full coverage of all coding exons of the DGKE gene 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 full 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).

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).