SLC25A13-Related Disorders via the SLC25A13 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
15293 SLC25A13 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15293SLC25A1381479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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 - Sequencing with CNV PG-Select

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.

Testing Strategy

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.

Indications for Test

Patients with clinical and biochemical features of NICCD, FTTDCD or CTLN2 are good candidates for this test. Family members of patients known to have SLC25A13 pathogenic variants are also good candidates, and we will sequence the SLC25A13 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
SLC25A13 603859
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Citrin Deficiency AR 605814
Citrullinemia Type II AR 603471

Citations

  • Dimmock D. et al. 2009. Molecular Genetics and Metabolism. 96: 44-9. PubMed ID: 19036621
  • Human Gene Mutation Database (Bio-base).
  • Kobayashi K. et al. 2003. Molecular Genetics and Metabolism. 80: 356-9. PubMed ID: 14680984
  • Kobayashi K. et al. 2014. Citrin Deficiency. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301360
  • Song Y.Z. et al. 2013. Plos One. 8: e74544. PubMed ID: 24069319
  • Tabata A. et al. 2008. Journal of Human Genetics. 53: 534-45. PubMed ID: 18392553
  • Tazawa Y. et al. 2004. Molecular Genetics and Metabolism. 83: 213-9. PubMed ID: 15542392
  • Woo H.I. et al. 2014. Clinica Chimica Acta; International Journal of Clinical Chemistry. 431: 1-8. PubMed ID: 24508627

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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