MYZAP was evaluated for autosomal recessive (AR) dilated cardiomyopathy (DCM). MYZAP is an intercalated disc (ID) protein that is required to maintain cardiac function. MYZAP is strongly expressed in the heart and localizes to the ID. At the time of this review, dilated cardiomyopathy is the only condition that has been associated with this gene.
At least 5 variants (all predicted or proven null) have been reported in humans with DCM. Two Spanish sibs with compound heterozygous LOF variants (one canonical splice donor and one novel nonsense) and DCM diagnosed in their 30’s. Western blot showed low expression of the splice variant and immunofluorescence testing showed abnormal subcellular localization of the nonsense variant (Ochoa et. al, 2024, PMID: 38436102). Two Slovenian siblings with severe, early-onset DCM and a novel homozygous truncating MYZAP variant. IHC and Western blot showed complete absence of MYZAP protein in the proband’s sample (Maver et. al, 2022, PMID: 35840178). Two Finnish families with two different homozygous truncating variants and a total of 4 individuals with confirmed DCM. Myocardium samples showed loss of myzap-staining compared to controls (Helio et. al, 2021, PMID: 34899865).
In addition, these gene-disease assertion is supported by expression studies and animal models. MYZAP KO zebrafish developed cardiomyopathy with pericardial edema and loss of contractility with normal morphology and severe skeletal muscle dysfunction (Seeger et. al, 2010, PMID: 20093627).
In summary, there is moderate evidence to support this gene-disease relationship. more evidence is needed to establish the relationship between MYZAP and AR DCM definitively. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 08/23/2024 (SOP Version 10).
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