Genotype-Negative Patients With Familial Hypertrophic Cardiomyopathy: Traveling to the "Middle Earth"

Area of Science:

• Cardiology
• Genetics
• Clinical Medicine

Background:

• A significant portion of hypertrophic cardiomyopathy (HCM) patients with negative genetic testing (Sarc-) have a positive family history (FH), indicating a potential genetic influence.
• This observation suggests that genetic factors beyond those typically identified may play a role in HCM development.

Purpose of the Study:

• To investigate whether patients with hypertrophic cardiomyopathy, negative genetic testing, and positive family history (Sarc-/FH+) exhibit distinct clinical phenotypes and prognoses.
• To compare Sarc-/FH+ patients with those who are genetically negative and have no family history (Sarc-/FH-) and those with positive genetic testing (Sarc+).

Main Methods:

• A cohort of 654 HCM patients underwent clinical assessment and genetic testing.
• Patients were categorized into three groups: Sarc-/FH-, Sarc-/FH+, and Sarc+.
• Follow-up for a median of 6 years assessed major arrhythmic events, heart failure, death, atrial fibrillation, and stroke.

Main Results:

• The Sarc-/FH+ group (15%) shared some characteristics with the Sarc+ group (younger age, higher risk of sudden cardiac death, less obstruction) but resembled the Sarc-/FH- group in other aspects (lower female prevalence, more cardiovascular risk factors, less late gadolinium enhancement).
• No significant differences in major adverse events were observed between the groups, except for a higher incidence of stroke in the Sarc+ group compared to the Sarc-/FH- and Sarc-/FH+ groups.
• The Sarc-/FH+ group presented intermediate clinical features between the Sarc-/FH- and Sarc+ groups.

Conclusions:

• The Sarc-/FH+ group represents a distinct subgroup of HCM patients with a mixed genetic and environmental influence.
• This population offers a valuable model for identifying novel genes and understanding non-genetic factors that modify HCM.
• Dedicated research into the Sarc-/FH+ population is crucial for advancing HCM understanding and management.