Steroid-Resistant Nephrotic Syndrome and Coenzyme Q10 Deficiency via the COQ8B/ADCK4 Gene

Nephrotic syndrome is a genetically heterogeneous disease defined by proteinuria, hypoalbuminemia, hyperlipidemia, and edema (Benoit et al. 2010; Santín et al. 2011; Saleem 2012). Approximately 20% of cases are steroid-resistant nephrotic syndrome (SRNS), characterized by resistance to steroid treatment and rapid progression to end-stage renal failure. The prevalent histological feature of SRNS is focal segmental glomerulosclerosis (FSGS), which has been seen in approximately 60% of SRNS cases. Diffuse mesangial sclerosis (DMS) is the other important histological feature associated with SRNS. The clinical courses of SRNS vary greatly with a wide range of age at onset from birth to adulthood.

COQ8B/ADCK4-associated SRNS develops through Coenzyme Q10 deficiency (Ashraf et al. 2013). Recessive mutations in COQ8B resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Early diagnosis is important because it may represent a form of SRNS that can potentially be treated by CoQ10 supplementation.

COQ8B-associated SRNS is an autosomal recessive disorder (Ashraf et al. 2013). The COQ8B gene encodes the aarF domain containing kinase 4, which interacts with members of the CoQ10 biosynthesis pathway in podocytes. So far, genetic defects of COQ8B found in SRNS include missense, nonsense mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving COQ8B have not been reported.

All of proteins encoded by SRNS-associated genes are localized to the podocytes, which are essential in maintaining the glomerular filtration barrier. Regarding protein function and location in podocytes, COQ8B belongs to both slit diaphragm-associated proteins and mitochondrial proteins (Malaga-Dieguez et al. 2013).

Detection rate of pathogenic variants in the COQ8B gene in a large cohort of patients with SRNS is unknown in the literature because documented COQ8B pathogenic variants have only been reported in limited cases. Analytical sensitivity should be high as all reported mutations are detectable by sequencing.

This test provides full coverage of all coding exons of the COQ8B 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).