Table.

Benefits and Limitations of HCM Genetic Testing

BENEFITS Definitive genetic diagnosis and identification of at-risk family members Pathogenic Mutation Present: At risk for disease development Follow for development of HCM Screen for SCD risk when appropriate 50% chance of transmission to each offspring Pathogenic Mutation Absent: Not at risk Not at risk for disease development or transmission to offspring Longitudinal clinical screening not required (consider re-evaluation if significant clinical change) Reproductive planning Prenatal or preimplantation diagnosis Confirmation of diagnosis/Identification of the genetic etiology of cardiac hypertrophy Potential to resolve ambiguous clinical diagnoses (e.g. hypertensive heart disease, athlete’s heart, metabolic/storage CMP) and guide therapy Greater understanding of disease Provides insight into fundamental disease biology Facilitate development of novel treatment strategies to change natural history and prevent disease

LIMITATIONS Limited clinical yield A mutation will not be identified in all patients with HCM Highest yield (up to ~70%): (+) family history of HCM and classic clinical features Lowest yield: no family history, very early or late onset disease, apical hypertrophy (sarcomere mutations uncommon) Negative results are non-informative Current methods may miss certain types of mutations Not all genes associated with HCM are known or analyzed Clinical family screening may still be appropriate-genetic etiology cannot be excluded Limited Clinical Impact Penetrance is variable and unpredictable Mutation ≠ Disease Few robust genotype-phenotype correlations Knowledge of the exact mutation typically does not significantly change management or provide accurate prognostic information Results may be Ambiguous: Variants of Unknown Significance Unclear if DNA variant is pathogenic (disease causing), disease modifying, or a benign polymorphism Results cannot be used for family management Segregation analysis in the family (with clinical and genetic evaluation) may help clarify pathogenicty Absence of the variant in an affected relative indicates the variant is not the cause of disease