MIB1 was originally evaluated for DCM by the ClinGen DCM GCEP on November 8, 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on October 4, 2024. As a result, the classification changed from no known disease relationship to limited. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.
MIB1 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2013 (Luxan et al. PMID: 23314057). Human genetic evidence supporting this gene-disease relationship includes case-level data. Four variants (2 missense, 1 splice site, 1 truncating) have been reported in humans in 2 studies (Luxan et al. PMID 23314057, Hazebroek et al. PMID: 29540472). Segregation was demonstrated in 2 families in Luxan et al. although, interestingly, most affected relatives had isolated left ventricular hypertrabeculation, and it was only the probands from both families that had contractile dysfunction. Functional evidence was demonstrated for these 2 variants. Importantly, this paper did not exclude truncating TTN variants. Further, this gene appears to be tolerant of loss of function variants. Hazebroek et al. identified two MIB1 variants in people with non-dilated hypokinetic cardiomyopathy, without segregation or functional evidence. None of these variants were scored in the last curation due to insufficient DCM phenotype. While there have been no new publications demonstrating an association between MIB1 and DCM since the last curation, on re-evaluation of the genetic data, the 2024 working group thought the described phenotypes were reasonable and a small number of points were warranted for this genetic evidence. This gene disease association is supported by a mouse animal model (Luxan et al. PMID 23314057, Captur et al. PMID: 27020702), and expression studies (Luxan et al. PMID 23314057, Jin et al. PMID: 12351649). In summary, despite no new evidence, on re-curation of the genetic evidence for MIB1 and AD DCM, the expert panel have upgraded this gene-disease classification to Limited. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 4 October, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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