Autosomal Recessive Transient Infantile Liver Failure (LFIT) via the TRMU 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
15405 TRMU 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15405TRMU81479 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

Transient infantile liver failure (LFIT) is characterized by acute hepatic failure and hyperlactatemia in 2 to 4-month old infants (Zeharia et al. 2009). Hallmark features of LFIT include feeding difficulties, growth delay, lethargy, jaundiced sclerae, hepatomegaly, and a distended abdomen (Zeharia et al. 2009; Gaignard et al. 2013). Additionally, patients present with high levels of lactate in cerebrospinal fluid and/or blood, indicative of mitochondrial dysfunction. To date, fewer than 30 patients have been identified with LFIT worldwide (Zeharia et al. 2009; Gaignard et al. 2013; Grover et al. 2015; Uusimaa et al. 2011; Kemp et al. 2011).

Given the rarity of this disorder, the long-term prognosis for a LFIT-affected child is still uncertain. In one study, however, LFIT patients who survived the initial acute hepatic event fully recovered normal liver function within 3-4 months, and did not have a second episode (longest follow-up: 14 years) (Zeharia et al. 2009).

Genetics

Transient infantile liver failure (LFIT) is an autosomal recessive disorder linked to defects in mitochondrial tRNA modification (Zeharia et al. 2009). The TRMU gene, located on chromosome 22q13.31, spans 11 exons and produces a mitochondrial-specific tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase. This enzyme is essential for the 2-thiolation of uridine at the wobble position of the mitochondrial tRNA-Lys, tRNA-Glu, and tRNA-Gln (Umeda et al. 2005; Sasarman et al. 2011). Consequently, loss or inactivation of TRMU results in severe reduction of this post-transcriptional modification, although the exact molecular consequence of such a defect is still in dispute (Zeharia et al. 2009; Sasarman et al. 2011).

A number of different pathogenic variants have been documented for TRMU-associated LFIT. Missense variants that alter highly conserved residues are documented most frequently; in particular, the variants c.229T>C (p.Tyr77His) and c.835G>A (p.Val279Met) are commonly reported (Zeharia et al. 2009; Gaignard et al. 2013; Grover et al. 2014; Uusimaa et al. 2011). Several other types of inactivating variants have also been described, including small out-of-frame insertions/deletions or splicing variants (Zeharia et al. 2009; Uusimaa et al. 2011; Gaignard et al. 2013).

A thorough differential diagnosis for LFIT is critical to rule out causative infections or similar genetic disorders. Heritable, non-reversible infantile liver failure has been associated with mitochondrial DNA depletion syndrome, which can be caused by loss-of-function variants in nuclear-encoded genes such as DGUOK, POLG, and MPV17 (Mandel et al. 2001; Naviaux and Nguyen 2004; Spinazzola et al. 2006). In contrast to the genetic disorders linked to these genes, TRMU-associated transient infantile liver failure patients have normal mtDNA levels (Zeharia et al. 2009).

Clinical Sensitivity - Sequencing with CNV PG-Select

Clinical sensitivity for transient infantile liver failure (LFIT) is difficult to estimate, as fewer than 30 patients have been described to date (Zeharia et al. 2009; Gaignard et al. 2013; Grover et al. 2014; Uusimaa et al. 2011; Kemp et al. 2011). Analytical sensitivity is expected to be high, however, as many of the pathogenic variants reported are either missense changes or small deletions/insertions.

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 TRMU 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

TRMU sequencing should be considered for patients who present with acute liver failure within the first few months of life, or for individuals with a family history of transient infantile liver failure. We will also sequence the TRMU gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
TRMU 610230
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Liver Failure Acute Infantile AR 613070

Citations

  • Gaignard P. et al. 2013. JIMD Reports. 11: 117-23. PubMed ID: 23625533
  • Grover Z. et al. 2015. JIMD Reports. 21: 109-13. PubMed ID: 25665837
  • Kemp J. et al. 2011. Brain: A Journal of Neurology. 134: 183-95. PubMed ID: 21169334
  • Mandel H. et al. 2001. Nature Genetics. 29:337-41. PubMed ID: 11687800
  • Naviaux R. and Nguyen K. 2004. Annals of Neurology. 55: 706-12. PubMed ID: 15122711
  • Sasarman F. et al. 2011. Human Molecular Genetics. 20: 4634-43. PubMed ID: 21890497
  • Spinazzola A. et al. 2006. Nature Genetics. 38: 570-5. PubMed ID: 16582910
  • Umeda N. et al. 2005. The Journal of Biological Chemistry. 280: 1613-24. PubMed ID: 15509579
  • Uusimaa J. et al. 2011. Journal of Medical Genetics. 48: 660-8. PubMed ID: 21931168
  • Zeharia A. et al. 2009. American Journal of Human Genetics. 85: 401-7. PubMed ID: 19732863

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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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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