TRIM37

Inheritance Pattern: AR

Disease ID:MONDO:0009664

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009664

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009664

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009664

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009664

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009664

Submitter: ClinGen

The relationship between TRIM37 and Mulibrey Nanism, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of February, 2020. TRIM37 encodes a member of the tripartite motif family. Mulibrey nanism is a multi-organ defect affecting the muscles, liver, brain, eye (Braverman et al, 2012, Gene Reviews) and characterized by severe growth failure of prenatal onset, characteristic dysmorphic features, perimyocardial heart disease, metabolic syndrome and hepatomegaly (Kallijarvi et al, 2006; PMID: 16514549). TRIM37 was first reported in relation to autosomal recessive mulibrey nanism in 2000. (Avela et al, PMID: 10888877). At least 20 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans in the ClinVar database. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 8 probands in 4 publications (PMID: 27256967, 17100991, 15108285, 10888877). More evidence is available in the literature, but the maximum score (12 points) for genetic evidence is reached. Two founder mutations in the Finnish population have been described: c.493-2A>G, referred to as the Finnish major mutation is most frequently seen, and Glu738fs, referred to as the Finnish minor mutation. The mechanism for disease is expected to be biallelic loss of function. Summary of experimental data (2 points): This gene-disease association is supported by in vitro functional assays and animal models. TRIM37 is shown to partially localize with the proxisome and interact with PEX5 to ubiquitylate it. Depletion of TRIM37 is shown to result in peroxisomal matrix protein import defect (PMID: 28724525). Mouse models of TRIM37 recapitulate the human disease; however no overt peroxisome pathology is noted (PMID: 27044324). In summary, TRIM37 is definitively associated with autosomal recessive mulibrey nanism. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Peroxisomal Disorders GCEP on May 1, 2020 (SOP Version 7).