Published in the journal Circulation and led by Dr. Soledad García-Hernández as first author and Dr. Juan Pablo Ochoa as senior author and study coordinator, the work aims to address the enigma of cases where no clear causal variant is found.
September 2, 2025.
Hypertrophic cardiomyopathy (HCM) is one of the cardiac diseases with the strongest genetic component. In many cases, it follows an autosomal dominant inheritance pattern, although a clear family history is not always observed due to factors such as incomplete penetrance, variable expressivity, or the occurrence of sporadic cases.
For decades, genetics has been key to understanding HCM, particularly through the discovery of variants in sarcomeric genes such as MYH7 or MYBPC3. However, despite these advances, a clear causal variant is identified in less than 40% of cases. What about the remaining patients?
A recently published study in Circulation provides a new answer: intermediate-effect variants. The work was led by Dr. Soledad García-Hernández, a cardiologist at Health in Code and at the Hospital Universitario Clínico San Cecilio in Granada. Dr. Juan Pablo Ochoa, Clinical Advisor at Health in Code and researcher at the National Center for Cardiovascular Research (CNIC), served as study coordinator and senior author.
What are intermediate-effect variants?
When we talk about genetic variants, we usually distinguish between two extremes:
- Pathogenic or likely pathogenic (P/LP): DNA changes that, on their own, cause the disease. Most carriers will eventually develop HCM.
- Benign: Variants with no relevant biological effect.
Intermediate-effect variants occupy a position between these two extremes. They are not harmless, but they do not determine the disease on their own. Carriers have a higher risk of developing HCM, although the penetrance is lower than that of classically pathogenic variants.
These variants were not studied before because they fell into a gray area: they were too common and considered of uncertain significance (VUS) or directly benign, and were not reported in genetic studies. At the same time, they were not frequent enough to be evaluated in GWAS studies used to construct polygenic scores.
The role of intermediate-effect variants in hypertrophic cardiomyopathy
According to Dr. Juan Pablo Ochoa, these variants could explain between 5% and 10% of hypertrophic cardiomyopathy (HCM) cases that are currently considered genetically negative. Moreover, they modulate phenotypic expression: in combination with classic pathogenic variants, the disease often presents in a more severe form.
We still have much to learn about their role in other diseases, but their relevance does not appear to be limited to HCM. There is evidence suggesting that in other cardiomyopathies (dilated, arrhythmogenic) and even in channelopathies such as long QT syndrome, these variants could also play a significant role.
Enrichment analysis: how to detect intermediate-effect variants
Identifying intermediate-effect variants is not straightforward. They often also appear in healthy individuals, which complicates interpretation. To address this, researchers applied an enrichment analysis: they genotyped thousands of HCM patients versus controls, evaluating whether certain variants were significantly more frequent in affected individuals.
The result was clear: some intermediate-effect missense variants were between 2 and 15 times more common in HCM patients than in the general population.
Clinical implications of intermediate-effect variants
Although many of these variants are already detected because the genes involved are included in clinical panels, the difference now lies in how to interpret and report them. Until now, they were often dismissed as “too frequent” for a classic Mendelian model. This study shows that we should start considering them systematically, creating repositories that capture their effect and frequency.
Regarding clinical practice, Dr. Ochoa remains cautious: “We are working on a position paper with guidance on how to manage patients carrying this type of variant.” For the time being, patients with these variants should be managed the same way as those with a negative genetic study. That is, follow-up should be based on clinical evaluation and family assessment, until clear recommendations become available.
Looking to the future
This work opens a new line in cardiovascular genetics: intermediate-effect variants fill the gap between classic monogenic diseases and complex polygenic models. Their study will help explain more cases, better understand clinical variability, and ultimately provide more precise counseling for patients and their families.
In the words of Dr. Juan Pablo Ochoa: “These variants are going to be very relevant because they complete the architecture of these diseases, sitting between monogenic and polygenic models. We will see many studies involving them in the coming years.”
This study represents a paradigm shift in the genetics of HCM. Intermediate-effect variants, previously in an interpretive limbo, are beginning to take their rightful place: an essential piece for understanding hypertrophic cardiomyopathy.
You can consult the publication available online here.
