TMOD1

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: ClinGen

TMOD1 was evaluated for autosomal recessive dilated cardiomyopathy (DCM). TMOD1 encodes tropomodulin 1 which plays a critical role in regulating actin filament length. At the time of review, dilated cardiomyopathy is the only condition that has been associated with this gene. Human genetic evidence supporting this gene-disease relationship includes case-level and variant-level functional data through one primary publication (Vasilescu et al, 2024, PMID: 38168645). In brief, a singleton non-consanguineous proband with DCM of Finnish ancestry was identified to be homozygous for a TMOD1 missense variant via proband-only whole exome sequencing with previously uninformative panel sequencing. Parents of the proband were confirmed to be heterozygous carriers via Sanger sequencing. Variant-level functional evidence was available for this observed missense variant through actin capping polymerization and depolymerization assays completed on human derived cardiomyocyte model generated via induced pluripotent stem cells from the observed patient in comparison to control fibroblasts. In brief, recombinant human TMOD1 revealed weaker rates in capping function in polymerization assays and weaker inhibition function in depolymerization compared to controls. Additional evidence was available immunofluorescence analysis of GFP-expressing rat cardiomyocytes expressing the variant in comparison to wild-type TMOD1 that revealed abnormal thin filament length in GFP-variant expressing cardiomyocytes supporting deleterious effect. TMOD1 variation in multiple families with well-established DCM phenotype, segregation or co-segregation data, and case control data has not been described. In addition, this gene-disease assertion is supported by tissue expression and biochemical function evidence, non-human model data, and evidence of TMOD1 protein interaction with genes previously associated with DCM across 6 primary publications. Sung et al. 1996 provided evidence of expression in human tissue with highest expression identified in the heart muscle followed by skeletal muscle via northern blot analysis (Sung et al, 1996, PMID: 8661028). Sussman et al. 1998 investigated effects of alteration of TMOD via recombinant adenoviral vectors expressing either sense (AD+TMOD) or antisense (AD-TMOD) cDNA. Imaging via immunofluorescence and electron microscopy revealed abnormal sarcomere and myofibril organization. In brief, AD+TMOD revealed loss of myofibrillar density, abnormal alignment and abnormally shortened sarcomeres, while AD-TMOD revealed abnormally long filaments and disorganized myofibrils (Sussman et al, 1998, PMID: 9440708). Additionally, Sussman et al. went on to establish a non-human model of DCM via homozygous transgenic mice overexpressing TMOD known as TOT. TOT mice at 3-4 days of age via echocardiography revealed significant hemodynamic differences compared to controls of left ventricular dilation and impaired systolic function consistent with a DCM phenotype (Sussman et al, 1998, PMID: 9421465). After the development of this model, TOT mice have been subjected to additional studies. Ehler et al. 2001 investigated TOT mice with electron microscopy, immunofluorescence, and immunoblotting as a part of a secondary analysis in a study that aimed to primarily investigate a muscle LIM protein, MLP. Results in TOT mice in this study supported biochemical functional importance in intercalated disc morphology and maintenance with TOT mice revealing altered protein composition including decreased connexin-43 and increased NRAP expression (Ehler et al, 2001, PMID: 11352937). Additional primary publications have suggested TMOD interaction with two additional protein products from DCM-associated genes, tropomyosin (moderate evidence) and LMOD2 (definitive evidence). Through electron microscopy and rotary shadowing, TMOD1 was identified to bind to tropomyosin, later clarified to occur at the N-terminus of TPM1, and actin-binding assays with increasing presence of TMOD revealed an inhibitory effect on TPM1 function (Fowler et al, 1990, PMID: 2380244). Similarly, Tsukada et al. 2010 utilized transfected cardiomyocytes to primarily investigate LMOD function; however through immunofluorescence microscopy of GFP-cardiomyocytes transfected with TMOD and overexpressed LMOD revealed antagonistic function between the two proteins, with overexpression in LMOD2 reducing TMOD staining suggestive of competing function (Tsukada et al, 2010, PMID: 20736303). Evidence of antagonistic, inhibitory function of TMOD with these independent DCM-associated genes previously identified to result from loss-of-function further supports this gene-disease assertion. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of TMOD with autosomal recessive DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 2, 2025 (SOP Version 10).