Genetic, Clinical, and Sociodemographic Profile in Individuals with Diagnosis or Family History of Hypertrophic Cardiomyopathy: Insights from a Prospective Cohort
Authors: Santos Emerson de Santana , Kuhn Gabriel da Costa , de Almeida Antônio Guilherme Cunha , Andrade Pimentel João Victor , Figueiredo Neto Newton Vital , Melo Bráulio Cruz , de Oliveira Daniel Pio , Galvão Gonçalves Luiz Flávio , Leite Aragão Ana Beatriz , dos Santos Bárbara Letícia Lima , de Araujo Pereira Beatriz Carolina , Soares Beatriz Luduvice , Ferreira Caio da Silva , Junior Donizete Ferreira de Sousa , Dias Costa João Paulo , Teixeira Barros Júlia Maria , Diniz Júlia Souza , da Silva Tavares Larissa Rebeca , Smith Lima Laís Prado , Xavier Luana Dias , Cardozo Barros Pedro Lucas , Silveira Campos Silvia Sayonara , Sales Vinícius Barbosa dos Santos , Leão e Silva Willian Moreira , Sab Yussef , de Melo Enaldo Vieira , Silva Tavares Irlaneide da , Sousa Antônio Carlos Sobral , Menezes Oliveira Joselina Luzia 
Published: January 2025

Background

Hypertrophic Cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy without secondary causes. Diagnosis relies on imaging techniques, such as echocardiography or cardiac magnetic resonance imaging (MRI), which show a maximal end-diastolic wall thickness ≥15 mm in adults. Wall thicknesses of 13– 14 mm may also support the diagnosis in individuals with a family history of HCM or sudden cardiac death (SCD), factors that strongly predict positive genetic test results and guide genetic testing decisions. However, current guidelines advise against routine genetic testing in phenotype-negative relatives unless there is a confirmed genetic diagnosis in the proband or testing is directed by a cardiovascular genetics expert. This study analyzes the genetic, clinical, and epidemiological profiles of individuals with HCM (positive phenotype) or asymptomatic patients with a family history of SCD or unconfirmed HCM.

Methods

We analyzed HCM patients, as defined by the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline, and asymptomatic individuals with a family history of SCD or unconfirmed HCM, performing genetic testing with a 19-gene panel to assess pathogenic mutations and implications for family screening and management.

Subjects with HCM, as defined by the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guidelines, or those with a negative phenotype but a positive family history of sudden cardiac death (SCD) or unconfirmed HCM, underwent genetic testing using a 19-gene panel associated with HCM and its phenocopies.

Results

Among 200 participants (58% male, median age 52 years), pathogenic/probably pathogenic variants were identified in 62 (31% – [95% CI: 24.7 to 37.9]), classified as “positive genotype,” 81 (40.5%) had variants of uncertain significance (VUS), and 57 (28.5%) had negative results. Of the total, 130 (65%) met ACC/AHA clinical criteria for HCM, while 70 (35%) had only a family history of SCD or unconfirmed HCM. Positive genotype rates were 37.7% in HCM-diagnosed individuals and 18.6% in those with a negative phenotype but positive family history (p = 0.006). Among positive genotypes, 77.4% involved sarcomeric genes (primarily MYH7 and MYBPC3, 79.2%), and 22.6% involved phenocopy-related genes, predominantly TTR (92.9%), linked to cardiac amyloidosis. Family history of SCD was more frequent in positive genotypes (68%) than negative genotypes (46%, p = 0.004). Median interventricular septal thickness was 17 mm in positive genotypes and 15 mm in negative genotypes (p < 0.001).

Conclusion/Discussion

The frequency of pathogenic variants in sarcomeric genes aligns with existing literature, but TTR-related cardiac amyloidosis was notably higher, suggesting greater prevalence in this population. Interventricular septal thickness >17 mm and a family history of SCD were strong predictors of positive genetic tests. While genetic testing should be guided by family screening and counseling, a family history of SCD or unconfirmed HCM may justify testing, especially when a pathogenic variant is identified in a family member.