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This summary reviews the association between C10orf71 and dilated cardiomyopathy, integrating genetic and functional studies. The evidence originates from both detailed family studies and large-scale multi‐patient analyses, underscoring the gene’s pathogenic role in cardiac contractile function (PMID:38950288).
In a large family, eight patients affected by DCM were identified through whole‐exome sequencing, providing strong segregation evidence. This familial evidence is further bolstered by the identification of loss‐of‐function variants in an additional cohort of 492 sporadic DCM patients (PMID:38950288).
The genetic evidence is underscored by the detection of frameshift events, exemplified by the representative variant c.772_790del (p.Ser258TrpfsTer39), which meets all the stringent HGVS requirements. This variant, along with other loss‐of‐function alterations, supports a mechanism of haploinsufficiency contributing to the DCM phenotype.
Functional assessments provide compelling support: C10orf71 knockout mice exhibit abnormal heart morphogenesis and adult cardiac dysfunction that closely resemble the human phenotype. Moreover, cardiomyocytes and heart organoids derived from induced pluripotent stem cells carrying C10orf71 frameshift variants display contractile defects, and rescue experiments using omecamtiv mecarbil have successfully restored function (PMID:38950288).
The integration of familial segregation, multi‐patient genetic analyses, and diverse experimental models yields a coherent and robust narrative. The convergence of these data reinforces that loss‐of‐function in C10orf71 is causative of dilated cardiomyopathy, with clear implications for diagnosis and personalized therapeutic strategies.
Key Take‑home Sentence: The strong association between C10orf71 loss‐of‐function variants and dilated cardiomyopathy establishes it as a critical diagnostic marker and a promising target for tailored interventions in DCM.
Gene–Disease AssociationStrongEight affected individuals in a familial setting (PMID:38950288) combined with four loss-of-function variants identified in 492 sporadic DCM patients (PMID:38950288) support a strong gene-disease association. Genetic EvidenceStrongFrameshift and loss-of-function variants detected in both familial (8 patients) and sporadic (492 cases) cohorts provide compelling genetic evidence for C10orf71's role in DCM (PMID:38950288). Functional EvidenceStrongFunctional studies in C10orf71 knockout mice and patient-derived heart organoids demonstrate impaired cardiomyocyte contractility, which is rescued by omecamtiv mecarbil, underscoring the pathogenic mechanism (PMID:38950288). |