Mitochondrial Complex I Deficiency via the NDUFAF1 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 this disorder may account for roughly one-third of all oxidative phosphorylation (OXPHOS) disorders (Skladal et al. 2003; Scaglia et al. 2004).

Significant clinical and genetic heterogeneity is observed among patients with inherited CI deficiency. The majority of patients present with a severe, rapidly progressive disease course within the first year of life. Organs with high energy requirements (such as the brain, heart, skeletal muscles, and/or eyes) are often the primary affected targets, and the most common clinical presentations include Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis, hypertrophic cardiomyopathy, and exercise intolerance (Fassone and Rahman 2012). Similar to other OXPHOS disorders, overproduction of lactic acid is a prevalent finding in patients with CI deficiency.

NDUFAF1-associated mitochondrial CI deficiency has been reported in only three unrelated individuals to date (Dunning et al. 2007; Fassone et al. 2011; Wu et al. 2016). Patients presented during the neonatal or infantile stages with hypertrophic cardiomyopathy, leukodystrophy, or cardioencephalopathy.

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, and at least 33 genes have been shown to be involved in this disease to date (Fassone and Rahman 2012).

NDUFAF1-associated mitochondrial complex I deficiency is inherited in an autosomal recessive pattern. NDUFAF1 (also referred to as CIA30) encodes an assembly factor of the mitochondrial complex I (Dunning et al. 2007). At least six causative variants have been described in this gene, including five missense variants and one splicing variant (Dunning et al. 2007; Fassone et al. 2011; Wu et al. 2016; Human Gene Mutation Database).

At this time, due to the limited number of reported cases, the clinical sensitivity of NDUFAF1-related mitochondrial complex I deficiency is difficult to estimate. All reported NDUFAF1 pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the NDUFAF1 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).