DTNA was originally evaluated for DCM by the ClinGen DCM GCEP on 10/25/2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 04/04/2025. As a result, the classification was changed from limited to no known disease relationship. A summary of the information contributing to the classification of this gene at the time of reevaluation is summarized herein.
In addition to DCM, DTNA has also been reported with left ventricular noncompaction, with or without congenital heart defects (AD, MIM 604169) and myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis (AD, MIM 620971). For the purposes of ClinGen lumping and splitting criteria, LVNC was considered to be a distinct cardiomyopathy based on its distinct morphological characteristics. The curation was split and curated for AD DCM. DTNA has also been curated by the Congenital Heart Disease GCEP for congenital heart disease (AD) (Disputed, 02/06/2024).
There is a lack of robust human genetic evidence demonstrating this gene-disease relationship in the literature at the time of this curation. At least 7 unique variants have been reported in humans, however these variants were not scored due to lack of clinical data for DCM and lack of comprehensive genetic testing for DCM (Xing et. al, 2006, PMID: 16427346; Cao et. al, 2017, PMID: 29118297; Dal Ferro et. al, 2017, PMID: 28416588; Walsh et. al, 2017, PMID: 27532257; Neubauer et. al, 2021, PMID: 33895855; Lesurf et. al, 2022, PMID: 35288587; Malakootian et. al, 2022, PMID: 35148685; Krishnaswamy et. al, 2024, PMID: 38551768).
This gene-disease association has limited support from expression studies in a non-human model organism, however this overexpression mouse model focuses on LVNC (Cao et. al, 2017, PMID: 29118297).
No convincing evidence for a causal role for DTNA and AD DCM has been reported. Rationale: reviewed case studies either lack sufficient clinical detail or provide no evidence to directly implicate genetic variation in DTNA as a cause of AD DCM in humans.This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 04/04/2025 (SOP Version 10).
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