Mitochondrial Complex I Deficiency via the NDUFB3 Gene

Mitochondrial complex I (CI) deficiency is characterized by a deficiency of the first and largest of the oxidative phosphorylation complexes (Fassone and Rahman 2012). Isolated mitochondrial CI deficiency is the most frequently reported childhood-onset mitochondrial disease, and may account for roughly one-third of all oxidative phosphorylation disorders (Skladal et al. 2003; Scaglia et al. 2004).

NDUFB3-associated isolated mitochondrial CI deficiency has been reported in fewer than 20 patients to date (Haack et al. 2012; Calvo et al. 2012; Alston et al. 2016). All affected individuals presented with infantile-onset lactic acidosis, which was occasionally sporadic or associated with intercurrent illnesses. Hypotonia, developmental delays, encephalopathy, and/or hypertrophic cardiomyopathy were also identified in some patients (Haack et al. 2012; Alston et al. 2016). 

The mitochondrial respiratory chain complex I (nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase) is composed of at least 45 structural subunits (Fassone and Rahman 2012). 38 of these subunits are encoded by nuclear DNA, and 7 are encoded by mitochondrial DNA. The resulting holoenzyme complex plays a critical role in redox-driven proton translocation, which ultimately results in synthesis of adenosine triphosphate (ATP; Sazanov 2015). Due to the many structural and accessory subunits required to support the assembly and function of complex I, mitochondrial CI deficiency is a genetically heterogeneous disorder. At least 33 genes have been shown to be involved in this disease to date (Fassone and Rahman 2012).

NDUFB3 encodes a structural subunit of the mitochondrial complex I, and NDUFB3-associated mitochondrial complex I deficiency is inherited in an autosomal recessive manner. Two causative variants (one missense and one nonsense variant) have been reported in this gene (Haack et al. 2012; Calvo et al. 2012; Human Gene Mutation Database). The pathogenic p.Trp22Arg variant was identified in eight different families of Irish descent, likely indicating a founder mutation (Alston et al. 2016). 

At this time, due to the limited number of reported cases, the clinical sensitivity of NDUFB3-related mitochondrial complex I deficiency is difficult to estimate. The few reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the NDUFB3 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).