Autosomal Recessive Transient Infantile Liver Failure (LFIT) via the TRMU Gene

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).

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 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.

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.