Mitochondrial Complex I Deficiency via the NDUFS4 Gene

Mitochondrial complex I (CI) deficiency is characterized by 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, which 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.

NDUFS4-associated mitochondrial CI deficiency has been reported in approximately thirty patients to date. The majority of patients presented during the neonatal or infantile stages with 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; Anderson et al. 2008). 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 NDUFS4 (Petruzzella et al. 2001; Scacco et al. 2003).

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 linked to this disease to date (Fassone and Rahman 2012).

NDUFS4-associated mitochondrial complex I deficiency is inherited in an autosomal recessive pattern. The NDUFS4 gene encodes a subunit of the mitochondrial complex I that must be phosphorylated by cAMP-dependent protein kinase for activation of the complex (Papa et al. 2002). At least 15 causative variants have been reported in this gene, including missense, nonsense, and splicing variants; small deletions and duplications; one indel; and two gross deletions (Human Gene Mutation Database).

At least two NDUFS4 founder pathogenic variants have been described. One single nucleotide deletion (c.462delA) has a carrier frequency of 1 in 1,000 in the Ashkenazi Jewish population (Anderson et al. 2008). An aberrant splicing variant, c.99-1G>A, has been reported in multiple families of Moroccan ancestry (Assouline et al. 2012; Bénit et al. 2003). Other variants, such as c.291delG (p.Trp97*), have been identified in multiple affected individuals from unrelated families, possibly indicating the presence of additional founder pathogenic variants in this gene (Budde et al. 2000; Assouline et al. 2012; Scacco et al. 2003).

At this time, due to the limited number of reported cases, the clinical sensitivity of NDUFS4-related mitochondrial complex I deficiency is difficult to estimate.

This test provides full coverage of all coding exons of the NDUFS4 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).