Carnitine-Acylcarnitine Translocase Deficiency via the SLC25A20 Gene

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder of long-chain fatty acid oxidation (Vitoria et al. 2015; Murphy et al. 2016). CACT deficiency most commonly presents as a severe neonatal disorder, though a small proportion of patients may present later with more mild disease (Iacobazzi et al. 2004; Korman et al. 2006; Vitoria et al. 2015). Patients with severe CACT deficiency present with cardiomyopathy and cardiac arrhythmias that can lead to sudden death, muscle weakness, hypotonia, respiratory distress, seizures, hepatomegaly, lethargy, and possible coma. Episodic attacks of hypoketotic hypoglycemia with hyperammonemia, metabolic acidosis, increased creatine phosphokinase (CPK) levels and elevated transaminases are observed, and are often triggered by fasting or illness. Patients may also exhibit dicarboxylic acidurias well as low levels of free carnitine and an abnormal acylcarnitine profile, particularly with increased C_16-18 acylcarnitines (Huizing et al. 1997; Vitoria et al. 2015; Murphy et al. 2016). Later onset patients may range from mildly symptomatic to asymptomatic (Iacobazzi et al. 2004; Vitoria et al. 2015).

Management of the disorder typically involves limiting dietary long-chain triglycerides, supplementation with medium-chain triglycerides and other essential fatty acids, prevention of fasting, especially during illness, and treatment of symptoms (Vitoria et al. 2015; Murphy et al. 2016).

CACT deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the SLC25A20 gene. Approximately 40 pathogenic variants have been reported to date. Approximately half of the pathogenic variants are missense or in-frame deletions or insertions, followed by small frameshift deletions or insertions (~30%), splice variants (~15%) and nonsense variants (~10%) (Human Gene Mutation Database). Two variants have been reported to be more prevalent than others: c.199-10T>G is common in East Asian populations and p.Gln238Arg is common in Arab patients (Vitoria et al. 2015). There may be some level of genotype-phenotype correlation, with more severely affected patients having a lower level of residual CACT enzyme activity and mildly affected patients having a higher level of residual enzyme activity, although this does not always seem to be the case (Vitoria et al. 2015).

The SLC25A20 gene encodes the carnitine-acylcarnitine translocase (CACT) protein, which is part of the carnitine shuttle. CACT functions by exchanging long-chain acylcarnintine esters that were generated via the action of carnitine palmitoyltransferase 1 (CPT1) for carnitine. This results in the transport of acylcarnitines across the inner mitochondrial membrane into the mitochondrial matrix, where they are converted back to acyl-CoAs via the action of carnitine palmitoyltransferase 2 (CPT2) (Murphy et al. 2016).

Clinical sensitivity of SLC25A20 gene sequencing is expected to be high for patients with carnitine-acylcarnitine translocase deficiency, as to date, nearly all reported patients have had two pathogenic variants detectable via sequencing. Based on a collective total of several studies, 75 alleles were reported in 38 unique patients, for a clinical sensitivity of ~99% (Huizing et al. 1997; Ogawa et al. 2000; Yang et al. 2001; Costa et al. 2003; Iacobazzi et al. 2004; Korman et al. 2006; Wang et al. 2011; Fukushima et al. 2013; Vatanavicharn et al. 2015; Vitoria et al. 2015). The one allele not detectable via sequencing was a large, multi-exon deletion (Wang et al. 2011).

It is difficult to precisely estimate the clinical sensitivity of this test as to date, only one confirmed gross deletion has been reported in the SLC25A20 gene (Wang et al. 2011), and no gross insertions have been reported. However, the clinical sensitivity appears to be relatively low.

This test provides full coverage of all coding exons of the SLC25A20 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).

In addition to the regions described above, this testing includes coverage for the reported intronic c.843+4_843+50del pathogenic variant (Iacobazzi et al. 2004).

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).