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TOP1MT encodes a mitochondrial topoisomerase that is essential for the regulation of mitochondrial DNA replication, transcription, and translation. Disruption of these functions can impact mitochondrial homeostasis, a key factor in the etiology of hypertrophic cardiomyopathy (PMID:36030054).
Genetic evidence supporting the association comes from exome sequencing of a newborn with hypertrophic cardiomyopathy, in which two missense variants in TOP1MT were reported. One such variant, c.1012G>T (p.Val338Leu), was identified alongside another variant, c.592C>T (p.Arg198Cys). The presence of these variants in a single unrelated proband (PMID:36030054) provides initial support for the gene-disease link, although familial segregation data are currently lacking.
Segregation analysis in this case is limited, with no additional affected relatives reported to carry the implicated variants. This limits the genetic evidence to a single proband, thereby constraining the overall weight of the genetic findings (PMID:36030054).
Functional studies using TOP1MT knockout cells have provided further insight into the pathogenicity of the identified variants. In these assays, neither variant was capable of fully rescuing mitochondrial-encoded protein levels or restoring oxidative phosphorylation. Notably, while one variant showed a modest improvement in mtDNA copy number, the overall loss-of-function effect observed in vitro supports a pathogenic mechanism consistent with hypertrophic cardiomyopathy (PMID:36030054).
When integrating both the genetic and functional evidence, the association between TOP1MT and hypertrophic cardiomyopathy is supported by a demonstration of impaired enzyme activity in a cellular model. However, the genetic evidence is currently limited to a single proband without segregation data, which restricts the overall confidence in the association and underscores the need for additional studies involving larger cohorts and family analyses.
Key take‑home: Although functional deficits in TOP1MT align with the disease phenotype, the clinical utility of this association remains limited until further genetic evidence, such as additional unrelated cases and familial segregation studies, is available.
Gene–Disease AssociationLimited1 proband with hypertrophic cardiomyopathy carrying TOP1MT variants was reported without additional familial segregation (PMID:36030054). Genetic EvidenceLimitedTwo missense variants, including c.1012G>T (p.Val338Leu), were identified in a single patient, representing limited genetic evidence for a causal relationship (PMID:36030054). Functional EvidenceModerateIn vitro rescue experiments in TOP1MT knockout cells demonstrated impaired function of the variants, supporting a loss-of-function mechanism relevant to disease pathology (PMID:36030054). |