Case of the Month: July

Bridging Clinical Suspicion and Genetic Testing in the Diagnosis of Inherited Cardiovascular Disease

Clinical Summary:

A patient presented with abdominal distension and pedal edema without breathlessness and was clinically suspected to have Danon disease based on the presenting cardiac phenotype. The family history was significant for sudden cardiac death in the father and multiple relatives with cardiovascular disorders, suggesting a possible inherited cardiac condition. Given the overlapping clinical features of inherited cardiomyopathies and arrhythmia syndromes, Inherited Cardiovascular Gene panel was performed to identify the underlying genetic etiology.

Clinical History:

The patient presented with abdominal distension and pedal edema in the absence of breathlessness. Family history revealed sudden cardiac death in the father at 67 years of age, along with hypertension and diabetes in both parents and grandparents. Additional cardiac-related illness was reported in the maternal grandmother and maternal uncle, although the exact diagnosis was unavailable. Based on the clinical presentation and family history, an inherited cardiomyopathy, particularly Danon disease, was considered in the differential diagnosis.

Genetic Findings:

Cardiovascular gene panel identified a heterozygous variant in the ANK2 gene. Variants in ANK2 are associated with ANK2-related cardiac arrhythmia syndrome, including Long QT syndrome type 4, an autosomal dominant inherited disorder characterized by abnormalities of cardiac electrical conduction, ventricular arrhythmias, syncope, and an increased risk of sudden cardiac death. No clinically significant variants were identified in the LAMP2 gene, which is associated with Danon disease.

Clinical Interpretation:

Although the patient's presentation initially raised suspicion for Danon disease, the genetic findings suggested an alternative inherited cardiac disorder involving the ANK2 gene. Both conditions may exhibit overlapping clinical manifestations, including cardiomyopathy, conduction abnormalities, heart failure symptoms, and an increased risk of sudden cardiac death, making clinical distinction difficult. Comprehensive genomic testing helped refine the differential diagnosis by identifying a gene associated with inherited cardiac arrhythmia syndromes, thereby directing attention toward appropriate cardiac rhythm evaluation in addition to structural cardiac assessment.

Conclusion:

This case highlights the value of gene sequencing in the evaluation of inherited cardiac disorders with overlapping clinical phenotypes. Comprehensive genomic analysis can broaden the differential diagnosis beyond the initial clinical suspicion, support more targeted clinical investigations, facilitate personalized patient management, and enable appropriate genetic counseling and family risk assessment. It also emphasizes the importance of integrating detailed clinical evaluation with molecular findings for optimal diagnosis and management.