Steroid-Resistant Nephrotic Syndrome and Coenzyme Q10 Deficiency via the COQ2 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.

Coenzyme Q10 deficiency is primarily characterized by neurological and muscular symptoms and has been associated with three main clinical phenotypes: a predominantly myopathic form with central nervous system involvement, an infantile encephalomyopathy with renal dysfunction, and an ataxic form with cerebellar atrophy (Quinzii et al. 2006; Desbats et al. 2015).

Recessive mutations in the COQ2 gene can cause a primary glomerular disease (COQ2 nephropathy), including early-onset SRNS, with variable renal lesions through coenzyme Q10 deficiency (Diomedi-Camassei et al. 2007).

COQ2-associated coenzyme Q10 deficiency is an autosomal recessive disorder (Quinzii et al. 2006; Diomedi-Camassei et al. 2007). The COQ2 gene (7 coding exons) encodes para-hydroxybenzoate-polyprenyl transferase in the coenzyme Q10 synthesis pathway. Genetic defects documented to date in COQ2 only include missense, nonsense variants and small indels (Human Gene Mutation Database).

All 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, COQ2 belongs to mitochondrial proteins (Malaga-Dieguez et al. 2013).

Detection rate of pathogenic variants in the COQ2 gene in a large cohort of patients with coenzyme Q10 deficiency is unknown in the literature because documented COQ2 pathogenic variants have been reported only 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 COQ2 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).