LDB3 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2003 (Vatta et al, PMID: 4662268). LDB3 was originally evaluated for DCM by the ClinGen DCM GCEP on May 22, 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on March 21, 2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. 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 AD DCM. LDB3 has also been curated by the ClinGen DCM GCEP for AR DCM. Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 7 unique missense variants have been reported in humans (Vatta et al, 2004, PMID: 4662268; Arimura et al, 2004, PMID: 14660611; Xing et al, 2006, PMID: 16427346). However, the majority of these variants were not assigned points due to high population frequencies in gnomAD or lack of functional data to support pathogenicity. Points were awarded to two de novo variants: p.Lys136Met and p.Thr213Ile (Vatta et al, PMID: 4662268). In addition, this gene-disease assertion is supported by expression studies, in vitro functional assays, protein interaction studies, and rescue in 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). 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 limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of LDB3 with AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on March 21, 2025 (SOP Version 10).
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