GET3 was evaluated for autosomal recessive dilated cardiomyopathy (DCM). GET3 is a cytosolic chaperone that mediates insertion of TA (tail-anchored) proteins into the endoplasmic reticulum (ER) membrane. Homozygous KO mice were embryonic lethal, whereas heterozygous mice did not exhibit a phenotype. Two siblings affected with childhood onset, quickly progressing dilated cardiomyopathy had compound heterozygous variants in GET3 that segregated with disease. GET3 expression in both patients’ samples was markedly reduced compared to controls. GET3 KO zebrafish showed abnormal cardiac contractions and decreased blood flow, thinner walls and less organized Z-lines with irregular intercalated discs compared to heterozygous clutchmates. None of the homozygous fish survived past 8dpf. Injection of wild-type human GET mRNA into GET3 KO zebrafish embryos significantly rescued the phenotype, whereas injection with either mutant mRNA had no significant effect. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of GET3 with AR DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 07/26/2024 (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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