Mitochondrial Phosphate Carrier Deficiency via the SLC25A3 Gene

Mitochondrial phosphate carrier deficiency is a rare inherited disorder characterized by hypertrophic cardiomyopathy, muscular hypotonia, and lactic acidosis (Seifert et al. 2015; Mayr et al. 2007; Mayr et al. 2011; Bhoj et al. 2015). In contrast to other mitochondrial disorders that cause cardiomyopathy, mitochondrial phosphate carrier deficiency patients retain normal oxidative phosphorylation (OXPHOS) complex activities and do not exhibit neurocognitive involvement.

To date, fewer than ten individuals with this disorder have been reported worldwide. In these patients, the disease was detected during prenatal ultrasound investigation or presented shortly after birth.

Mitochondrial phosphate carrier deficiency is an autosomal recessive disorder caused by defects in the mitochondrial phosphate carrier gene SLC25A3 (Mayr et al. 2007; Mayr et al. 2011). The mitochondrial phosphate carrier (also referred to as PiC) catalyzes the transport of phosphate into the mitochondrial matrix, a porcess that is essential for the aerobic synthesis of adenosine triphosphate (ATP). The SLC25A3 gene has two tissue-specific alternative isoforms, known as PiC-A and PiC-B. Both isoforms have 7 coding exons, although each isoform carries a unique third exon. PiC-A is predominantly found in heart and skeletal muscle; in contrast, PiC-B is ubiquitously expressed, with highest levels in the lung and thyroid (Dolce et al. 1996).

Several causative missense variants, one splicing variant, and one small deletion/insertion have been reported in SLC25A3 to date (Human Gene Mutation Database). Two reported SLC25A3 causative variants (c.215G>A and c.158-9A>G) only affect exon 3A of PiC-A (Mayr et al. 2011). All other reported pathogenic variants may affect both the PiC-A and PiC-B isoforms (Mayr et al. 2007; Bhoj et al. 2015)

The clinical sensitivity for this test is difficult to estimate, as pathogenic variants in the SLC25A3 gene have been reported in fewer than ten individuals to date (Mayr et al. 2007; Mayr et al. 2011; Bhoj et al. 2015). Analytical sensitivity is expected to be high, however, as all of the pathogenic variants reported in these patients can be detected via sequencing.

No gross deletions or insertions have been reported in the SLC25A3 gene to date (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SLC25A3 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).