Sex- and Age-Specific Genetic Risk Across Dilated and Arrhythmogenic Cardiomyopathy: Insights From the SHaRe Registry

Overview

Dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) are inherited or acquired diseases of the heart muscle that can lead to heart failure, dangerous rhythm problems, and, in some cases, sudden cardiac death. Although these conditions have traditionally been studied separately, they often overlap in how they appear clinically and genetically. This study from the SHaRe Registry explored an important question: do sex and age influence which genetic variants are most common in DCM/ACM, and when the disease first appears?

The short answer is yes. The researchers found that sex-related differences are not uniform across all genes. Some genetic variants were more common in males, others in females, and the age at diagnosis also varied by genotype. These findings may help clinicians think more carefully about individualized screening and surveillance, especially in families with a known pathogenic variant.

Why this study matters

DCM is characterized by enlargement and weakening of the ventricles, usually the left ventricle, which reduces the heart’s pumping ability. ACM is best known for fibrofatty replacement of heart muscle and a high risk of arrhythmias, often involving the right ventricle but sometimes affecting both ventricles. In real-world practice, many patients do not fit neatly into only one of these categories. Some have features of both, and many disease-causing genes can produce overlapping phenotypes.

Previous work has shown a male predominance in both DCM and ACM, but it has been unclear whether that is due to biology, referral bias, differences in disease stage at presentation, or gene-specific effects. It has also been uncertain whether boys and girls, men and women, develop disease at different ages depending on the underlying mutation. This study helps answer those questions using a large, multicenter registry.

How the study was done

Researchers analyzed adults and children enrolled in the SHaRe registry, a large international registry of sarcomeric and related cardiomyopathies. The cohort included patients with DCM or ACM who had genetic testing, as well as asymptomatic relatives who were found to carry a disease-associated variant.

The team evaluated sex distribution across 27 genes linked to DCM and ACM using logistic regression. They also compared the age at diagnosis across sex and genotype using Kaplan-Meier cumulative incidence methods. In practical terms, this allowed the investigators to study not just who had the disease, but also when it first became clinically apparent.

Key findings: sex differences across the genetic spectrum

Among 3,410 patients, there was an overall male predominance of 61% across genotype-positive, genotype-negative, and variants of uncertain significance groups. This male predominance was statistically significant, but it was not the same for every gene.

A major finding was that truncating variants in TTN, often called TTNtv, were less common in females. TTN encodes titin, a large structural protein essential for normal cardiac muscle function. TTN truncating variants are among the most common genetic causes of DCM. In this study, females were significantly less likely than males to carry TTNtv.

In contrast, variants in DSP and a group of non-TTN sarcomeric genes were more common in females. DSP encodes desmoplakin, a key desmosomal protein involved in cell-to-cell adhesion in the heart. The grouped non-TTN sarcomeric genes included ACTC1, TNNT2, MYH7, TNNC1, TNNI3, and TPM1. These genes are traditionally associated with contractile function and are often linked to cardiomyopathy phenotypes that may differ from TTN-related disease.

This pattern suggests that the observed male predominance in cardiomyopathy is not simply a universal biological rule. Instead, the sex distribution depends in part on which gene is involved.

Age at diagnosis: mostly similar, but not always

Across most genes, age at diagnosis was similar between males and females. However, one important exception stood out: TTNtv carriers.

Among patients with TTN truncating variants, males developed disease earlier than females. The median age at diagnosis in males was 45 years, compared with 51 years in females. This difference may reflect biological modifiers, environmental exposures, or sex-related differences in how the disease develops and is recognized clinically.

This finding is clinically relevant because TTNtv are common in DCM. If males carrying TTNtv tend to develop symptoms or detectable disease earlier, they may benefit from closer surveillance at younger ages. At the same time, females carrying the same variant should not be assumed to be protected; rather, they may present later or progress differently.

Pediatric-onset disease has a distinct genetic profile

The study also examined patients diagnosed before age 18 years. There were 174 pediatric-onset cases, and these children also showed a male predominance of about 60%. But the genetic pattern in children differed from that in adults.

Compared with adult-onset disease, pediatric-onset DCM/ACM was more likely to be associated with non-TTN sarcomeric variants and PKP2 variants. PKP2 encodes plakophilin-2, another desmosomal protein strongly linked to arrhythmogenic cardiomyopathy. The enrichment of these variants in pediatric disease suggests that early-onset cardiomyopathy may arise from a somewhat different genetic architecture than later-onset disease.

The age distribution in children was bimodal, with peaks in infancy and adolescence. That is an important observation. It implies that genetic cardiomyopathy can emerge at very different developmental stages, perhaps due to developmental changes in the heart, variable penetrance, or different modifying factors across childhood.

For clinicians, this means suspicion for genetic cardiomyopathy should remain high both in infants with unexplained heart failure and in adolescents with arrhythmias, exercise intolerance, syncope, or family history of inherited heart disease.

What these results may mean biologically

The reasons for sex-specific differences in genetic cardiomyopathy are not fully understood, but several mechanisms are plausible. Sex hormones may influence gene expression, myocardial remodeling, and electrical stability. Men and women may also differ in how the heart responds to mechanical stress, inflammation, or myocardial injury.

In addition, some variants may have sex-dependent penetrance, meaning that a person’s sex affects whether and when the disease becomes clinically visible. There may also be differences in lifestyle factors, exercise exposure, referral patterns, or thresholds for diagnosis that contribute to the observed patterns.

Importantly, the study did not prove why these differences occur. Rather, it showed that they exist and are specific to certain genes and age groups. This makes them a target for future mechanistic research.

Clinical implications

These findings have several practical implications for cardiology care:

1. Family screening may need to be gene-specific and sex-aware. A relative carrying a TTN truncating variant may benefit from a different surveillance plan than someone carrying a DSP or PKP2 variant.

2. Pediatric cardiomyopathy should not be viewed as simply “adult disease in smaller patients.” The genetic landscape is different, and early-life presentation may point to specific genes.

3. Sex should be considered as a meaningful biological variable in cardiomyopathy counseling. It may influence not just risk, but also age of onset and possibly disease course.

4. Patients with genotype-positive but phenotype-negative status should still undergo regular follow-up. A normal evaluation today does not eliminate future risk, especially in families with known pathogenic variants.

5. Adult and pediatric cardiomyopathy care should integrate genetics more deeply. Genetic results can help guide surveillance, family testing, exercise counseling, and decisions about rhythm monitoring or imaging frequency.

How this fits into current cardiomyopathy care

In current practice, evaluation of DCM/ACM often includes echocardiography, cardiac magnetic resonance imaging, electrocardiography, ambulatory rhythm monitoring, and genetic testing when inherited disease is suspected. Management may include guideline-directed medical therapy for heart failure, arrhythmia treatment, activity modification, implantable cardioverter-defibrillator placement in selected patients, and cascade testing of relatives.

This study does not change the fundamental treatments for DCM or ACM, but it strengthens the case for personalized surveillance. For example, a family with TTNtv may warrant earlier attention in males, while a family with DSP variants may require careful rhythm surveillance in females as well as males. For children, especially infants and adolescents, clinicians should remember that non-TTN sarcomeric variants and PKP2 may be particularly relevant.

Limitations

As with any registry-based study, there are limitations to keep in mind. Patients in the SHaRe registry may not represent all people with DCM or ACM in the general population. Referral patterns, genetic testing practices, and differences in disease severity could influence who entered the study.

In addition, the study focused on diagnostic age and genetic distribution, not on long-term outcomes such as heart failure progression, transplant, or sudden death. It also cannot fully distinguish biological sex effects from social or health-system effects. Despite these limitations, the sample size was large and the findings were consistent enough to be clinically meaningful.

Bottom line

This study shows that sex differences in DCM and ACM are real but gene-specific. TTN truncating variants were more common in males and were linked to earlier disease onset in male carriers. DSP and non-TTN sarcomeric variants were more common in females. In pediatric-onset disease, the genetic profile was distinct, with a stronger role for non-TTN sarcomeric and PKP2 variants and a bimodal onset pattern in infancy and adolescence.

The key message is that cardiomyopathy risk is not determined by a single factor. Sex, age, and gene type interact in important ways. Recognizing those interactions can improve family counseling, surveillance planning, and future research into why inherited heart disease behaves differently in different patients.