Dilated Cardiomyopathy

Gene: LDB3

I don't know

Limited ClinGen gene-disease validity for DCM - last assessed 09/2020 - https://search.clinicalgenome.org/CCID:005274
Monoallelic missense variants in LDB3 that affect only short isoforms are associated with skeletal myopathies while variants affecting only long isoforms have been identified in cardiomyopathies. Biallelic LoF variants associated with paediatric DCM (PMID: 36253531, 32922198 - a green gene on the paediatric cardiomyopathy panel).

The most compelling evidence for DCM association is 2 assumed de novo cases (but only LDB3 tested; PMID: 14662268). Functional evidence is limited because the knockdown animal models are more supportive of biallelic DCM. There is reported segregation evidence for AD DCM in 3 families, but only 1 of the variants is rare enough to be consistent with a dominant disease (PMID: 14662268, 14660611).

Relevant publications since 2016 (most recent in ClinGen assessment)
PMID: 35284542 - enrichment of LDB3 missense variants (n=5; some variants have been called LB or a bit common in gnomAD) in Chinese sporadic DCM cohort (n=66). Prevalence p=0.039. 24 DCM genes sequenced
PMID: 32041989 - DCM c.1189G>A; p.Val397Ile (1 het gnomAD v4) - VUS. 102 cardiomyopathy genes tested

PMID: 38551768, 38992921 - limited evidence for HCM association

Created: 27 Jul 2024, 2:16 a.m. | Last Modified: 27 Jul 2024, 2:16 a.m.

Panel Version: 1.33

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
dilated cardiomyopathy MONDO:0005021

Publications

• 14662268
• 14660611
• 35284542
• 32041989

I don't know

PMID 14662268: 1 family with DCM and LVH, 1 family with CMD, severe LVH, and LVNC, and 4 sporadic patients with CMD and LVH or LVNC.

PMID 14660611: 1 family with DCM had a missesnse variant in 3 affected and 1 unaffected family member.

PMID 16427346: 2 unrelated Japanese families with LVNC had the same missense variant.

PMID 26419279: 2 large Bedouin families with DCM and LVNC had a missense variant but it did NOT segregate with disease.

A quick look at some of these vairants showed the lowest gnomad frequency is 4 hets (others are 79, 173, and ~1300).

Created: 5 Aug 2020, 6:54 a.m. | Last Modified: 5 Aug 2020, 6:54 a.m.

Panel Version: 0.78

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Cardiomyopathy, dilated, 1C, with or without LVNC MIM#601493

Publications

• 26419279
• 16427346
• 14660611
• 14662268

Variants in this GENE are reported as part of current diagnostic practice