L-Cysteine supplementation prevents liver transplantation in a patient with TRMU deficiency

Purpose: A primary barrier to improving exome sequencing diagnostic rates is the interpretation of variants of uncertain clinical significance. We aimed to determine the contribution of integrated untargeted metabolomics in the analysis of exome sequencing data by retrospective analysis of patients evaluated by both whole exome sequencing and untargeted metabolomics within the same clinical laboratory. Methods: Exome sequencing and untargeted metabolomic data were collected and analyzed for 170 patients. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance in genes associated with a biochemical phenotype were extracted. Metabolomic data were evaluated to determine if these variants resulted in biochemical abnormalities which could be used to support their interpretation using current ACMG guidelines. Results: Metabolomic data contributed to the interpretation variants in 74 individuals (43.5%) over 73 different genes. The data allowed for the re-classification of 9 variants as likely benign, 15 variants as likely pathogenic, and 3 variants as pathogenic. Metabolomic data confirmed a clinical diagnosis in 21 cases, for a diagnostic rate of 12.3% in this population. Conclusion: Untargeted metabolomics can serve as a useful adjunct to exome sequencing by providing valuable functional data that may not otherwise be clinically available, resulting in improved variant classification.

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“…This approach resulted in an overall diagnostic rate of 12.3% (21/170 = 12.3% [ Table 1 ]). 10 , 13 , 16 – 18 …”

Section: Resultsmentioning

confidence: 99%

Integrated analysis of metabolomic profiling and exome data supplements sequence variant interpretation, classification, and diagnosis

Alaimo

Glinton

Liu

et al. 2020

Genetics in Medicine

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“…The TRMU gene encodes for the tRNA 5-methylaminomethyl-2-thiouridylate methyl-transferase, which is responsible for the 2-thiouridylation (addition of a sulfur-containing thiol group) of mt-tRNA Glu , mt-tRNA Gln and mt-tRNA Lys [6,7]. Autosomal recessive mutations in the TRMU gene cause abnormal mitochondrial protein translation.…”

Section: Introductionmentioning

confidence: 99%

Two genetic disorders (TRMU and SCYL1) explaining transient infantile liver failure in one patient

Campos¹,

Teles²,

Rodrigues³

et al. 2020

Int Med Care

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Introduction: Paediatric acute liver failure (PALF) has an extremely heterogeneous aetiology, with some genetic disorders being associated with recurrent/transient episodes of infantile hepatopathy. Here, we report a patient who experienced a severe episode of liver failure with complete recovery, and in whom were discovered two genetic disorders possibly explaining this occurrence: a mitochondrial disease caused by pathogenic variants in TRMU gene and the CALFAN syndrome secondary to mutations in SCYL1 gene.Case presentation: Healthy female child who was admitted at hospital by the age of 13 months due to acute hepatic failure in context of febrile flu. Hepatotropic infectious diseases were excluded and metabolic evaluation was normal, with exception of positive allopurinol testing. Liver biopsies revealed focal ballooning of hepatocytes and pronounced fibrosis. The liver function gradually recovered. From age of 3 years, she developed intention tremor, and after the age of 10 progressive ataxia and motor-sensory neuropathy. She is now 25 years-old and presents a cerebellar syndrome, without cognitive impairment. There were no further episodes of hepatic failure and serial evaluation showed normal liver function, without evidence of important fibrosis in transient elastography. Genetic analysis revealed that the patient has two novel variants in heterozygosity in TRMU gene, and, in homozygosity, an already known pathogenic variant in SCYL1 gene. Conclusion:Although patient presents neurological features of CALFAN syndrome, it is discussed which genetic disorder (SCYL1 or TRMU) was responsible for the acute liver failure episode.

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“…Classical presentation of TRMU pathogenic variants has been described to date in 26 patients with acute liver failure as the main phenotype, some of which share other clinical findings (Supplementary table) [ 2 , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] ]. Almost all (24/26) reported patients suffered from hepatic failure.…”

Section: Discussionmentioning

confidence: 99%

Leigh syndrome associated with TRMU gene mutations

Sala‐Coromina

Dougherty

Heras

et al. 2021

Molecular Genetics and Metabolism Reports

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tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency causes an early onset potentially reversible acute liver failure, so far reported in less than 30 patients. We describe two new unrelated patients with an acute liver failure and a neuroimaging compatible with Leigh syndrome (LS) due to TRMU deficiency, a combination not previously reported. Our report enlarges the phenotypical spectrum of TRMU disease.

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L-Cysteine supplementation prevents liver transplantation in a patient with TRMU deficiency

Cited by 16 publications

References 22 publications

Integrated analysis of metabolomic profiling and exome data supplements sequence variant interpretation, classification, and diagnosis

Integrated analysis of metabolomic profiling and exome data supplements sequence variant interpretation, classification, and diagnosis

Two genetic disorders (TRMU and SCYL1) explaining transient infantile liver failure in one patient

Leigh syndrome associated with TRMU gene mutations

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