SLC25A13-Related Disorders via the SLC25A13 Gene

Three distinct disorders have been associated with deficiency of the mitochondrial transporter protein citrin: NICCD, FTTDCD and CTLN2.

NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency) is found solely in infants approximately 12 months old and younger. Clinically, these patients present with transient intrahepatic cholestasis, growth retardation, diffuse fatty liver, hepatomegaly and other possible liver dysfunction. In the majority of patients, symptoms are not severe and resolve with dietary treatment by ~1 year of age. However, some patients may progress to cirrhosis of the liver requiring liver transplantation (Kobayashi et al. 2014). Biochemically, these patients may be detected via newborn screening due to any of the following: hypergalactosemia, hypermethioninemia, hyperphenylalaninemia, mild hyperammonemia, citrullinemia, or hypoproteinemia. Presumably as a result of the galactosemia, some patients also present with cataracts (Tazawa et al. 2004; Tabata et al. 2008). Neonatal citrin deficiency can be difficult to distinguish from other types of hepatic disease as these biochemical disturbances are not always present (Dimmock et al. 2009).

FTTDCD (failure to thrive and dyslipidemia caused by citrin deficiency) may occur during childhood in citrin deficient patients. Many patients may be asymptomatic, but others may present with growth retardation, hypoglycemia, fatigue, pancreatitis, fatty liver, hepatoma and marked food preferences for protein- and lipid-rich food over carbohydrates (Kobayashi et al. 2014).

CTLN2 (citrullinemia type 2, late-onset) has been reported with an age of onset between ~11-79 years of age, although clinical symptoms most typically begin between the ages of 20-50 years. CTLN2 patients may or may not have had a history of NICCD and/or FTTDCD. CTLN2 is the most severe disorder associated with citrin deficiency. These patients present with recurrent hyperammonemic episodes that are associated with neuropsychiatric symptoms such as nocturnal delirium, aggression, seizures, and unconsciousness, among others. Prognosis is generally poor and death due to brain edema often occurs within a few years of onset, although liver transplantation has been shown to be quite effective in ameliorating these symptoms. Biochemically, in addition to hyperammonemia, these patients tend to have increased plasma citrulline and arginine levels, an increased threonine to serine ratio, and increased pancreatic secretory trypsin inhibitor (PTSI) (Kobayashi et al. 2003; Tabata et al. 2008; Kobayashi et al. 2014).

Additionally, patients are suspected of having citrin deficiency if the activity of the argininosuccinate synthetase enzyme, encoded by the ASS1 gene, is found to be deficient in the liver but not renal tissue or fibroblasts (Dimmock et al. 2009). Several external factors, such as carbohydrate and alcohol intake, stress, medications and infections, can also affect the onset and course of disease (Woo et al. 2014).

SLC25A13-related disorders are all inherited in an autosomal recessive manner, and defects in the SLC25A13 gene are the only known cause (Kobayashi et al. 2014). The SLC25A13 gene encodes the liver-type mitochondrial aspartate/glutamate transporter protein called citrin (Song et al. 2013). Citrin deficiency is an overall rare disorder, with a higher occurrence in Japanese, Chinese and Korean populations, although it has been documented in other populations as well (Kobayashi et al. 2014). To date, nearly 100 pathogenic variants in the SLC25A13 gene have been reported in the literature. Nearly half of these variants are missense changes, with the remainder being nonsense and splice variants, small insertions, deletions and indels, as well as large copy number changes (Human Gene Mutation Database). Some of the most commonly reported variants include the c.851_854del variant, which is thought to have arisen due to a founder effect in East Asian countries, the splice variant c.1177+1G>A, and the nonsense variant c.674C>A (p.Ser225*). In addition, a retrotransposon insertion of 2,667 nucleotides (often designated IVS16ins3kb in the literature) has been reported to be relatively common in Japanese patients (Tabata et al. 2008; Woo et al. 2014). For unknown reasons, citrullinemia type 2 (CTLN2) seems to be more common in males than females, with an earlier age of onset in males. No clear genotype-phenotype correlation has been observed, even within affected members of the same family (Woo et al. 2014).

Clinical sensitivity of this test should be high in patients with citrin deficiency. Song and colleagues (2013) reported 117 pathogenic alleles out of a total of 120 alleles, suggesting a sensitivity of ~98%, whereas Dimmock et al. (2009) reported two pathogenic alleles in all 10 patients studied, for a sensitivity of 100%.

Several large deletions and insertions in the SLC25A13 gene have been reported to be causative for citrin deficiency (Human Gene Mutation Database). However, none appear to be frequent as most have been reported only in a single individual.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the SLC25A13 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.