BAG5

Inheritance Pattern: AR

Disease ID:MONDO:0030680

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0030680

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0030680

Submitter: ClinGen

BAG5 was evaluated for autosomal recessive dilated cardiomyopathy (DCM). BAG5, first described in 1999 (Takayama et al., 1999, PMID: 9873016), is a part of the BAG family of co-chaperones for Hsp70 and Hsc70 aiding in protein folding and trafficking regulation. At the time of review, dilated cardiomyopathy is the only condition that has been associated with this gene. Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 5 variants (nonsense, frameshift) have been reported in humans with DCM in a homozygous or compound heterozygous state. A total of 12 cases across 5 primary publications were reviewed. Two publications from Hakui et al. (Hakui et al., 2022, PMID: 35044787; Hakui et al., 2022, PMID: 36130910) detail 6 of the total reported cases reviewed. In addition, the BAG5 p.Arg197Ter variant first detailed in Hakui et al. 2022 was reported in 6 of the 12 cases reviewed across 3 primary publications in either a homozygous (Hakui et al., 2022, PMID: 35044787; Hakui et al., 2022, PMID: 36130910) or compound heterozygous state (Inoue et al., 2023, PMID: 37873655). While consanguinity was unknown for the homozygous cases, 3 of these cases were identified querying 536 DCM patients in an in-house Japanese database after transcriptomics identified BAG5 as an upregulated gene in tissue from DCM patients compared to controls (Hakui et al, 2022, PMID: 35044787). Frequency of this variant in a small, geographically isolated population suggests a possible founder variant. BAG5 loss-of-function variants were identified in remaining DCM proband cases via whole exome (Inoue et al., 2023, PMID: 37873655; Hakui et al., 2022, PMID 36130910; Wongwong et al., 2024, PMID: 38796549) or whole genome sequencing (Lesurf et al., 2022, PMID: 3588587). While majority of the 12 cases reviewed were from independent families, Wongwong et al., 2024 detailed clinical and genetic evidence from a large, consanguineous, Middle Eastern kindred with whole exome sequencing in 3 affected siblings and 2 unaffected parents, identifying a frameshift BAG5 variant consistent with biallelic loss-of-function. Sanger sequencing in nine additional relatives showed segregation of the variant with normal clinical phenotypes in a heterozygous or wild-type state (Wongwong et al., 2024, PMID: 38796549). In addition, this gene-disease assertion is supported by recapitulated disease phenotypes in animal models with phenotypic rescue, and functional data supporting protein-interaction with a previously curated, moderate-DCM gene, JPH2. Knock-in (KI) homozygous mice harboring the previously detailed p.Arg197Ter variant were created utilizing CRISPR-CAS9 methodology (Hakui et al., 2022, PMID: 35044787). Cardiac phenotypes of homozygous KI-mice were compared to wild-type mice via cardiac magnetic resonance imaging at 12 weeks and echocardiogram imaging from 5 to 12 weeks, identifying a phenotype consistent with DCM. Phenotypic rescue after administration of AAV9 vector carrying wild-type BAG5 and cardiac troponin T promoter (administered at 10 weeks) was successfully demonstrated with significant improvements in left ventricular diastolic diameter (reduction) and fractional shortening (increase) via echocardiogram at 12 weeks of age. Finally, a series of co-immunoprecipitations with HEK239T cells (harboring a different human variant, p.Arg390Ter) and isolated cardiomyocytes from the previously described mouse-model were completed to investigate interaction of specific substrates with the HSC70/BAG5 complex (Hakui et al., 2022, PMID 35044787). Utilizing primary HSC70 antibodies, co-IP experiments with wild-type and mutant HEK293T cells and co-IP experiments with wild-type and mutant isolated cardiomyocytes from the KI-mice model indicated reduced pull down of HSC70 and reduced pull down of JPH2 when mutant BAG5 was present. This data supports indirect interaction of BAG5 with JPH2 through the HSC70/BAG5 complex. In summary, there is moderate evidence to support this gene-disease relationship. More evidence is needed to establish the relationship of BAG5 with AR-DCM definitively. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 6/14/2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0030680

Submitter: PanelApp Australia