TSFM-Related Combined Oxidative Phosphorylation Deficiency via the TSFM Gene

Combined oxidative phosphorylation (OXPHOS) deficiency is a multi-systemic disorder characterized by reduced activity of two or more mitochondrial respiratory chain enzyme complexes. Pathogenic variants in over 30 different genes, primarily mitochondrial translation factors, have been linked to this disease.

TSFM-associated combined OXPHOS deficiency exhibits significant clinical heterogeneity. Patients may present with infantile encephalopathy, hypertrophic cardiomyopathy, early onset hepatic failure, and/or Leigh syndrome, a subacute necrotizing encephalopathy characterized by brain stem or basal ganglia involvement, lactic acidosis, and progressive neurologic disease (Ahola et al. 2014; Smeitink et al. 2006; Vedrenne et al. 2012). Despite this broad spectrum of possible clinical manifestations, all patients share distinctive biochemical abnormalities such as severe lactic acidosis and multiple respiratory complex deficiencies. Optic neuropathy, dystonia, ataxia, epilepsy, and cognitive impairment have also been occasionally reported in individuals with this disorder (Ahola et al. 2014; Smeitink et al. 2006).

Symptomatic onset of TSFM-associated combined OXPHOS deficiency usually occurs at birth or within the first year, although at least one affected individual first presented at the age of fifteen years (Ahola et al. 2014; Smeitink et al. 2006; Vedrenne et al. 2012). Due to the severe complications associated with this disease and a lack of treatment options, half of all reported patients died within the first two months following birth (Smeitink et al. 2012; Vedrenne et al. 2012). Individuals that survived into adulthood generally presented later in life with milder symptoms (Ahola et al. 2014).

Combined oxidative phosphorylation (OXPHOS) deficiency is an autosomal recessive, X-linked, or maternally inherited disease. Pathogenic variants in over 30 different nuclear and mitochondrial genes have been reported as causative for this disorder. The majority of these genes encode for elements of the mitochondrial translation apparatus or mitochondrial tRNAs or rRNAs.

Nuclear genes associated with autosomal recessive inheritance of combined OXPHOS deficiency include: AARS2, ATP5A1, BOLA3, C12orf65, EARS2, ELAC2, FARS2, GFER, GFM1, GTPBP3, ISCU, LYRM4, MARS2, MRPL3, MRPL44, MRPS16, MRPS22, MTFMT, MTO1, NARS2, NFU1, PARS2, PNPT1, PUS1, RMND1, SERAC1, SFXN4, TARS2, TRMT5, TSFM, TUFM, VARS2, and YARS2.

AIFM1 is the only gene associated with X-linked recessive inheritance of this disease.

Additionally, pathogenic defects in any of the mitochondrial-encoded tRNA genes (22 total) or rRNA genes (2 total) are expected to result in combined oxidative phosphorylation deficiency (Smits et al. 2010).

The nuclear TSFM gene encodes for the mitochondrial translation elongation factor S, which binds the EF-Tu:GDP complex during protein biosynthesis to facilitate the exchange of GDP for GTP (Akama et al. 2010). To date, one nonsense and two missense changes have been reported for TSFM-related combined oxidative phosphorylation deficiency (Ahola et al. 2014; Smeitink et al. 2006; Vedrenne et al. 2012). The pathogenic c.856C<T (p.Gln286*) variant is carried at an extremely high frequency (1:80) in Finnish populations; however, this variant has only been detected in compound heterozygotes or carriers (Ahola et al. 2014; Lim et al. 2014). No homozygotes were detected in a population study of over 35,000 Finns, indicating that the c.856C<T (p.Gln286*) variant is most likely lethal in the homozygous state during embryonic development (Lim et al. 2014).

TSFM-associated combined oxidative phosphorylation (OXPHOS) deficiency has been described in fewer than 10 individuals to date (Ahola et al. 2014; Smeitink et al. 2006; Vedrenne et al. 2012). Although we cannot precisely estimate clinical sensitivity at this time, pathogenic variants in TSFM appear to be a rare cause of combined OXPHOS deficiency.

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