Genotype–phenotype correlation in a single centre cohort of patients affected by hypertrophic cardiomyiopathy

Abstract Background Over the last 30 years, major advances have been made in the identification of the genetic basis of Hypertrophic Cardiomyopathy (HCM) and the spectrum of sarcomeric genes has been gradually extended to non–sarcomeric genes. Multiple attempts to identify genes with an unfavorable impact on prognosis failed; data for genotype–phenotype relationships are still insufficient. Objective Assess the clinical presentation and genotype–phenotype correlation of patients (pts) and the prognostic impact and clinical relevance of genetic tests. Methods 130 adults pts with HCM were enrolled from January 2019 to May 2023. The included patients underwent blood sampling for genetic investigation. Results 34 pts were HCM phenocopies (see figure 1). Our analysis was focused on the 96 (74%) pts with HCM. 40 pts carried likely pathogenetic/pathogenetic (LP/P) variants;23 pts carried a variant of uncertain significance; 33 pts had a negative genetic test. The majority of the pts carried MYH7 gene variants, followed by variants of MYBPC3 (see figure 1). Age at diagnosis had a significant effect on the likelihood of identifying a LP/P or VUS variant (54.44±12.7 for genetic test negative, 41.09±16.9 for VUS carriers, 35.4±15.3 for LP/P carriers, p.0.001). The presence of hypertension significantly affected the likelihood of identifying a negative genetic test (p 0.002). LP/P/VUS variants were significantly more common in patients with a family history of cardiomyopathies (p 0.001). 26% of VUS carriers and 17% of LP/P carriers had advanced heart failure; only 3% of patients with negative genetic test showed advanced heart failure (p 0.04). Carriers of LP/P variants showed more asymmetric hypertrophy, while patients with a genetic test negative showed more concentric hypertrophy. The composite endpoint (hospitalization for heart failure, cardiovascular death and cardiac transplantation) occurred in 8 (24.2%) patients with negative genetics, 16 (69.5%) patients with VUS and 14 (35%) patients with LP/P variants with a statistically significant difference (p=0.03) (see table 1). On multivariable analysis, having a positive genetic test (VUS/LP/P) was found to increase the probability of having the event by 3.8 fold compared to patients with a negative genetic test having a negative variant(see table 2). Conclusion We demonstrated the correlation between anamnestic data, cardiac phenotype and genotype. Genetic testing has also a prognostic value.