Mitochondrial Complex I Deficiency via the NDUFAF4 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).

NDUFAF4-associated mitochondrial CI deficiency has been reported in in six patients from two separate families (Saada et al. 2008; Haack et al. 2012). In one family, affected individuals presented during the neonatal period with lactic acidosis, hypotonia, failure to thrive, and nystagmus (Saada et al. 2008). At least one patient had severe cardiomyopathy, and another exhibited severe brain atrophy. In patients who survived to childhood, additional symptoms such as kyphosis, multiple contractures, and/or tonic-clonic convulsions were evident. In the second family, the affected individual presented with a Leigh-like syndrome (LLS) characterized by lactic acidosis, hypotonia, psychomotor developmental delay, bilateral symmetrical lesions in the brainstem and basal ganglia, and failure to thrive (Haack et al. 2012; Rahman and Thorburn 2015).

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).

NDUFAF4-associated mitochondrial complex I deficiency is inherited in an autosomal recessive manner. The NDUFAF4 gene (also referred to as C6ORF66 in the literature) encodes for an accessory protein involved in the assembly of mitochondrial complex I. Two causative variants, both missense changes, have been reported in this gene (Saada et al. 2008; Haack et al. 2012).

At this time, due to the limited number of reported cases, the clinical sensitivity of NDUFAF4-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 NDUFAF4 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).