Mitochondrial Complex I Deficiency via the NDUFV2 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). Overproduction of lactic acid is a common finding in patients with this disorder.

NDUFV2-associated mitochondrial CI deficiency has been reported in only four families to date (Bénit et al. 2003; Pagniez-Mammeri et al. 2009; Cameron et al. 2015). In two families, affected individuals presented during infancy with seizures and Leigh Syndrome (LS) (Cameron et al. 2015). LS is a severe, progressive encephalopathy characterized by a distinct set of diagnostic criteria, which include psychomotor delay or regression; isolated or combined mitochondrial complex deficiencies; elevated levels of lactate in the blood and/or cerebral spinal fluid; bilateral symmetrical lesions in the brainstem and basal ganglia; and neurologic manifestations such as hypotonia or ataxia (Rahman and Thorburn 2015; Lake et al. 2015; Cameron et al. 2015). In the remaining two families, affected individuals presented with early-onset hypertrophic cardiomyopathy and encephalopathy (Bénit et al. 2003; Pagniez-Mammeri et al. 2009).

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).

NDUFV2-associated mitochondrial complex I deficiency is inherited in an autosomal recessive pattern. The NDUFV2 gene encodes a structural subunit of the mitochondrial complex I flavoprotein fraction that is critical for catalytic function of the complex (de Coo et al. 1995). Only two causative variants, one small deletion and one small insertion, have been documented in this gene (Bénit et al. 2003; Cameron et al. 2015; Human Gene Mutation Database).

At this time, due to the limited number of reported cases, the clinical sensitivity of NDUFV2-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 NDUFV2 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).