"Double-hit" precipitates fulminant cardiac dysfunction in a child with homozygous CAP2 variant: a case report

Clinical evidence increasingly supports that in children harboring underlying dilated cardiomyopathy (DCM) associated genetic variants, respiratory viral infection frequently serves as the unmasking trigger, precipitating fulminant cardiac dysfunction. Herein, we report a case of DCM with a homozygous loss-of-function CAP2 variant which was firstly identified by virus infection triggered fulminant cardiac dysfunction. This case reinforces the link between cytoskeletal dysfunction and cardiac electromechanical failure, while also expanding the adverse impacts of virus infection in DCM long-term management.

The proband was a 5-year-old boy presented fulminant cardiac dysfunction. Respiratory pathogen panel was positive for rhinovirus. Exome sequencing (ES) identified a novel homozygous variant in CAP2 c.551G > A (p.W184*; NM_006366.3). The nonsense mutation resides within the N-terminal helical folded domain, resulting in complete truncation of the central and C-terminal regions. Abrogation of WH2 domain is predicted to completely abolish CAP2 function, impairing sarcomeric actin recycling and cytoskeletal integrity. Sustained intensive therapies could reverse ventricular remodeling conferred clinically significant functional benefit in this patient. Rather, the clinical trajectory of this patient is best interpreted through the lens of a "double-hit" pathogenic mechanism.

To our knowledge, this is the first report of the novel homozygous CAP2 c.551G > A (p.W184; NM_006366.3) variant associated with pediatric DCM. And the early genetic screening should be prioritized in children presenting with unexplained cardiac malformation, growth retardation, or a family history of consanguinity. Moreover, infection prevention and prompt intervention, including adherence to recommended vaccination schedules, are paramount in known DCM carriers.