Mitochondrial Complex I Deficiency via the NDUFV1 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).

NDUFV1-associated mitochondrial CI deficiency often presents as leukodystrophy, usually accompanied by lactic acidosis in the blood and/or cerebral spinal fluid (Ortega-Recalde et al. 2013; Schuelke et al. 1999). Another common clinical presentation is Leigh syndrome (LS), a severe, progressive encephalopathy characterized by a distinct set of diagnostic criteria (Rahman and Thorburn 2015). LS symptoms 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 (Lake et al. 2015; Keone et al. 2012). Leigh-like syndrome, which describes a similar clinical presentation in which one or more of these diagnostic characteristics is atypical, has also been reported in patients with pathogenic variants in NDUFV1 (Laugel et al. 2007).

Although age of onset may vary, patients with NDUFV1-related disorders generally present within the first year of life (Keone et al. 2012).

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 drives ATP synthesis within the cell (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 linked to this disease to date (Fassone and Rahman 2012).

NDUFV1-associated mitochondrial complex I deficiency is inherited in an autosomal recessive pattern. Defects in the NDUFV1 gene, which encodes for a structural subunit that carries the NADH-binding site of mitochondrial complex I, are frequently identified in cases of mitochondrial complex I deficiency (Koene et al. 2012; Schuelke et al. 1999). Approximately thirty different causative variants have been reported in NDUFV1 (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/ac/index.php). The majority of these variants are missense changes, although nonsense and splicing variants have also been described, in addition to several deletions.

In a review of the literature, Keone et al. noted that 17 of 130 mitochondrial complex I deficiency cases (~13%) were caused by pathogenic variants in NDUFV1 (Keone et al. 2012).

This test provides full coverage of all coding exons of the NDUFV1 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).