LDB3

Inheritance Pattern: AR

Disease ID:MONDO:0979236

Submitter: ClinGen

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. Although independent reports over a 3 year period contributed to this curation, the panel elected to classify as Strong to allow additional evidence to accumulate for this newly curated MOI for LDB3 before upgrading to a Definitive classification. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on March 21, 2025 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

Lim domain-binding 3 (*LDB3*) was first reported in relation to autosomal dominant hypertrophic cardiomyopathy (HCM) in 2006 (Theis et al., PMID 17097056). At least 5 variants (all missense) have been reported in humans. Variants in *LDB3* have been reported in individuals with the following disease entities: dilated cardiomyopathy (DCM), left ventricular noncompaction (also known as hypertrabeculation) and myofibrillar myopathy. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in phenotypic variability. Therefore, the following disease entity has been split, hyertrophic cardiomyopathy 24 OMIM:601493. A single family has been reported in the literature with an HCM phenotype and compound heterozygous LBD3 variation but there is insufficient evidence to alter the curated mode of inheritance (PMID 36452351). The split curation for autosomal dominant DCM OMIM:601493, and autosomal recessive DCM OMIM:621237 have been curated separately. Evidence supporting this gene-disease relationship includes case evidence (PMIDs 14662268, 17097056, 24730657) and experimental data (PMID 10427098). All but one case in this curation have population frequencies incompatible with pathogenicity (>0.0001) according to the ClinGen HCVD GCEP. Experimental evidence includes expression data showing almost equal expression in cardiac and skeletal muscle in addition to protein interaction data with ACTN2 which is curated for a syndromic form of skeletal and cardiac myopathy. Case-control data contradicts the gene-disease relationship however with no excess found of HCM cases with rare variation in *LDB3* compared to the ExAC control database (PMID 28082330). In summary, the evidence supporting the relationship between *LDB3* and autosomal dominant hypertrophic cardiomyopathy has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *LBD3* plays in this disease. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on the meeting date January 27, 2026 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0011094

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0012277

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0016333

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012277

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011094

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0979236

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

The association of LDB3 with ARVC is disputed. A study (25041374) investigated a family affected by ARVC on which Sanger sequencing failed to find a disease‐causing mutation in any of the five desmosomal genes in the proband (DSP, JUP, DSC2, DSG2, PKP2). The authors performed Next Generation Sequencing by using a 134 genes panel in order to discover a candidate disease‐causing gene. Genetic screening identified a missense variant on LDB3 causing the aminoacid substitution Thr351Ala, this variant was reported in ClinVar as conflicting interpretation (VUS, LB). This variant shows a high MAF in the general population to be associated with the disease even though the proband and family carriers do have ARVC. There is disputed evidence that the identified LDB3 variant contribute to the ARVC phenotype and there is no known disease mechanism that would link LDB3 with ARVC.

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012277

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0012277

Submitter: G2P