SUCLG2-Related Mitochondrial DNA Depletion Syndrome via the SUCLG2 Gene

Mitochondrial DNA (mtDNA) depletion syndromes are characterized by deficiencies in the maintenance or integrity of the mtDNA genome, resulting in a significant decrease in the abundance of mtDNA within the cell (El-Hattab et al. 2013). These diseases, which exhibit significant clinical and genetic heterogeneity, are caused by defects in nuclear-encoded genes. Depletion of mtDNA content impairs energy production in either a tissue-specific or multi-system manner. Clinical presentation of this disorder generally falls into one of four categories (myopathic, encephalomyopathic, hepatocerebral, or neurogastrointestinal), although initial symptoms may overlap between or progress into multiple categories depending on the gene(s) affected (Suomalainen et al. 2010). Onset ranges from the neonatal period to adolescence. The SUCLG2 gene encodes for the beta subunit of the GDP-forming isoform of the succinyl-CoA ligase (Miller et al. 2010). Variants responsible for human disease have not yet been reported in this gene, although pathogenic variants in two other succinyl-CoA ligase subunit genes, SUCLA2 and SUCLG1, are causative for mtDNA depletion syndrome (Ostergaard et al. 2007; Carrozzo et al. 2007). Given the close association of the SUCLG2 gene with SUCLA2 and SUCLG1, SUCLG2 has been included in our Mitochondrial Genome Maintenance/Integrity Nuclear Genes NextGen Sequencing (NGS) Panel (Test #1399).

Mitochondrial DNA (mtDNA) depletion syndromes are caused by pathogenic variants in nuclear genes such as TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, TYMP, POLG, C10orf2, MGME1, MPV17, AGK, and FBXL4 (El-Hattab et al. 2013; Kornblum et al. 2013; Mayr et al. 2012; Gai et al. 2013). These genes, in addition to SUCLG2, are covered by our Mitochondrial Genome Maintenance/Integrity Nuclear Genes NextGen Sequencing (NGS) Panel (Test #1399). Succinyl-CoA ligase, an enzyme of the citric acid cycle, catalyzes the reversible conversion of succinyl-CoA, phosphate, and ADP (or GDP) to succinate, coenzyme A (CoASH), and ATP (or GTP). This enzyme is composed of two subunits: an invariant alpha subunit encoded by SUCLG1 and a beta subunit encoded by either SUCLA2 or SUCLG2. Nucleotide specificity is determined by the beta subunit, resulting in the ADP- or GDP-forming isoforms of succinyl-CoA ligase, respectively. Although SUCLG2 pathogenic variants have not yet been reported, variants in SUCLG1 and SUCLA2 have been associated with autosomal recessive mtDNA depletion syndrome (Ostergaard et al. 2007; Carrozzo et al. 2007). Furthermore, knockdown of SUCLG2 by shRNA in vitro significantly decreases cellular mtDNA content, demonstrating that SUCLG2 may also play an important role in mitochondrial maintenance (Miller et al. 2010).

Pathogenic variants in SUCLG2 have not yet been identified. Therefore, we are unable to estimate clinical sensitivity at this time.

This test provides full coverage of all coding exons of the SUCLG2 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).