LMOD2 was evaluated for autosomal recessive dilated cardiomyopathy (DCM). LMOD2 encodes leiomodin 2, which is part of the leiomodin/tropomodulin protein family. LMOD2 is a thin filament actin-binding protein that plays a role in contraction in muscle (Tolkatchev et. al, 2022, PMID: 34273242). At the time of this review, dilated cardiomyopathy is the only condition that has been associated with this gene.
At least 4 unique variants (including in-frame indel, nonsense, and intronic) have been reported in 5 human probands with DCM. Individuals typically presented with severe infant onset DCM (Yuen et. al, 2022, PMID: Lay et. al, 2022, PMID: 35188328; Sono et. al, 2023, PMID: 37296576; Ahrens-Nicklas et. al, 2019, PMID: 31517052; Greenway et. al, 2022, PMID: 34888509). One case control study was evaluated for LMOD2 (Lipov et. al, 2023, PMID: 38666070). This study also provided evidence suggesting enrichment of LMOD2 truncating variants in ICD-coded DCM in UK Biobank under a dominant model (OR = 13.7, P = 7.8e-4). However, while this information was discussed and considered in regards to the final classification of LMOD2, this evidence was unable to be scored due to privacy policies of the biobank restricting the publication of case-control values due to the small cohort.
In addition, this gene-disease assertion is supported by expression studies, interaction studies, and animal models. Expression of LMOD2 in human heart tissue, as well as altered expression in patient tissues, was shown by western blot (Sono et. al, 2023, PMID: 37296576; Ahrens-Nicklas et. al, 2019, PMID: 31517052). Additionally, both a Lmod2-KO mouse model and Lmod2 piggyBac mutant mice were shown to have a DCM phenotype (Pappas et. al, 2015, PMID: 26487682; Li et. al, 2016, PMID: 27274810). Introduction of GFP-Lmod2 was also shown to rescue the DCM phenotype in Lmod2 KO mice (Pappas et. al, 2015, PMID: 26487682). Finally, an interaction between TPM1, a moderate gene for DCM, and LMOD2 was shown via NMR (Coplan et. al, 2016, PMID: 26873245).
In summary, LMOD2 is definitively associated with AR DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic setting and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 10/04/2024 (SOP Version 10).
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