Submission Details

LDB3 was first reported in relation to autosomal recessive dilated cardiomyopathy in 2023 (Koopmann et al, PMID: 36253531). In addition to DCM, LDB3 has also been reported with myofibrillar myopathy at the time of review. This was considered in accordance with ClinGen lumping and splitting criteria. Due to the distinct differences in phenotypic variability the curation was split and curated for AR DCM. LDB3 has also been curated by the ClinGen DCM GCEP for AD DCM. Human genetic evidence supporting this gene-disease relationship includes case-level data. At least four unique frameshift/truncation variants and one splice site have been reported in humans in homozygous or compound heterozygous state (Koopmann et al, PMID: 36253531). In addition, this gene-disease assertion is supported by expression studies, in vitro functional assays, protein interaction studies, and animal models. It has been well established LDB3 is expressed in the heart (Faulkner et al, 1999, PMID: 10427098, Zhou et al, 1999, PMID: 10391924, Huang et al, 2004, PMID: 12499364, Vatta et al, 2004, PMID: 4662268). Protein interaction studies show LDB3 interacts with ACTN2 (Faulker et al, 1999, PMID: 10427098, Zhou et al, 1999 PMID: 10391924, Zheng et al, 2009, PMID: 19028670, Zhou et al, 2001, PMID: 11696561) and TNNI3 (Lv et al, 2021, PMID: 34966794). Importantly, knockout animal models developed dilated cardiomyopathy and heart failure (Cheng et al., 2011, PMID: 21303826, Zhou et al, 2001, PMID: 11696561, Zheng et al., 2009, PMID: 19028670). Zebrafish and mouse animal rescue models showed injection of Cypher resulted in at least a partial rescue of the phenotype (Huang et al, 2004 PMID: 12499364, Van de Meer et al, 2006, PMID: 16982050). In summary, there is strong evidence to support the relationship between LDB3 and AR DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on March 21, 2025 (SOP Version 10).