FBXO32

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: ClinGen

FBXO32 was evaluated for autosomal recessive inheritance in dilated cardiomyopathy (DCM).At the time of this review, dilated cardiomyopathy is the only condition that has been associated with this gene. FBXO32 contains 9 exons, and is expressed across many tissues but strongly in muscle and heart (gnomAD.v4.1/GTEx). FBXO32 encodes F-box protein 32, also known as atrogin-1. It is a component of ubiquitin ligase complex, which facilitates ubiquitination and subsequent proteasome degradation of proteins, for instance misfolded proteins. The protein was initially studies in the context of muscle wasting, during which it is upregulated and known to target myosins. Human genetic evidence supporting this gene-disease relationship includes case-level data and segregation data, detailed below. At least 2 variants have been reported in humans with DCM. Ghasemi et al. (PMID 36344977) studied a consanguineous Iranian family with four siblings diagnosed with DCM; while relatively little phenotype detail was given for most, the proband had dilated LV at age 25 in absence of clear causes (including metabolic). Exome sequencing identified the FBXO32 c.884_886del variant in homozygous state, with also homozygous state in one other sibling with ‘DCM’; the variant was not found in homozygous state by Sanger sequencing in parents or 2 healthy siblings. Variants in TTN, MYH7, MYBPC3, BAG3 and LMNA were explicitly excluded in proband. Given a homozygous non-truncating variant without functional evidence in the DCM proband but given consanguinity, no case level points were assigned. Al-Yacoub et al. (PMID 26753747) studied a consanguineous Saudi family with four siblings with DCM (all dilated LVs with severe hypocontractility at young ages) among which 3 required heart transplants. The authors used genome-wide approaches, namely genome-wide linkage analysis using genotyping array in all siblings and parents, followed by exome sequencing in the proband. Only one linkage region was identified, which did not overlap any known DCM genes; exome sequencing identified a homozygous NM_058229.3:c. 727G > C, p.Gly243Arg variant in FBXO32. All four affected cases where found to be homozygous, while all other family members (parents and 5 unaffected siblings) were heterozygous or homozygous reference by Sanger sequencing. The variant was found in heterozygous state at very rare frequency in gnomAD v4.1 (10 carriers). The authors then performed Westerns blots, showing that FBXO32 showed decreased binding to known binding partners in HEK293 cells with mutant (p.Gly243Arg) FBXO32; similarly, cells from two affected siblings also showed a decreased patterns of FBXO32 binding to known binding partners. Al-Hassnan et al. (PMID 26768247) studies a consanguineous Saidi family with 4 siblings with severe LV dysfunction requiring transplant at young ages. Highly similar approaches were described as in Al-Yacoub et al., and the same homozygous p.Gly243Arg variant was identified in all affected siblings. Given very similar pedigree, approaches, and variant, there were concerns that the family did not present a distinct pedigree for case scoring. Al-Yacoub et al. and Al-Hassnan et al. both report segregation evidence, with LOD scores around 3.4. Given the issues described above, only Al-Yacoub was scored for segregation data. Al-Yacoub (PMID 26753747) showed using Western blot that FBXO32 is expressed in healthy and DCM heart tissues; Frustaci et al. (PMID 26764074) showed that mRNA levels are significantly different between control and DCM myocardial slices. Zaglia et al. (PMID 24789905) studied LV morphological, electrical, and cellular differences, between FBXO32-homozygous-knockout, heterozygous-knockout, and wild-type mice. Homozygous-knockouts developed significantly increased heart size, diastolic impairment, and LV enlargement (increased LVESD). Mice also developed increased fibrosis as well as substantially increased PVC burden. This showed a clear cardiomyopathic phenotype in homozygous knockout. It is noted that FBXO32 is strongly implicated in DCM and other cardiomyopathies through GWAS (eg. Jurgens et al. PMID 39572784), indicating that common genetic modifiers around the gene may play a role in pathogenesis. However, this is at current not a scorable criterion. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of FBXO32 and DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 05/30/2025 (SOP Version 10).