Expanding Knowledge on the Genetics of Hypertrophic Cardiomyopathy: A New Prevalent Intermediate-Effect Variant in the FHOD3 Gene

• The intermediate-effect variant p.Arg637Gln in the FHOD3 gene has been identified to increase the risk of developing hypertrophic cardiomyopathy and is associated with an aggressive phenotype in homozygous carriers.


• This conclusion comes from a new study led by Dr. Juan Pablo Ochoa, Medical Director at Health in Code, with Dr. Jesús Piqueras Flores as the lead author. The findings have been published in the Journal of Medical Genetics.



Madrid, January, 16, 2024.

In 2018, Dr. Juan Pablo Ochoa discovered the association between variants in the FHOD3 gene (formin homology domain containing 3) and the development of hypertrophic cardiomyopathy (HCM). The Argentine cardiologist, who is not only the Medical Director at Health in Code, but also a prominent scientist at CNIC and a cardiogeneticist at the Puerta de Hierro University Hospital, has now led a study involving several hospitals in Spain and Ireland, with Dr. Jesús Piqueras Flores, a cardiologist at the General University Hospital of Ciudad Real, as the first author.


The p.Arg637Gln FHOD3 variant is a low-frequency variant located in a relevant region of the gene, a cluster where disease-causing variants associated with HCM are found. It has a minor allele frequency (MAF) of 0.3%.


The study assessed the presence of the variant in a cohort of more than 22,000 independent probands sequenced by NGS, finding it more prevalent in patients with HCM compared to internal and gnomAD controls, with odds ratios greater than 5.   


This implies that carriers of this variant are approximately five times more at risk of developing HCM than non-carriers. Although a variant with very low penetrance, estimated at 1%, it could contribute significantly to the proportion of HCM cases (especially genotype-negative and sporadic).


Dr. Juan Pablo Ochoa explains, “We then looked for homozygous carriers and identified five probands in our cohort, all diagnosed with HCM. Except for one, all carriers exhibited severe phenotypes with a high incidence of ventricular arrhythmias.”


This information indicates that the p.Arg637Gln variant in FHOD3 is a low-penetrance variant with an intermediate effect, contributing to the development of HCM in simple heterozygosity and being associated with a more severe phenotype in homozygous carriers.



What Are Intermediate-Effect Genetic Variants?

Intermediate-effect variants are variants found with relative frequency in control populations but are overrepresented in certain phenotypes, which indicates an association with disease. They are not as common as the polymorphisms detected in GWAS (genome wide association studies), nor are they infrequent enough to be considered “monogenic” or “Mendelian.”


There is some debate on naming these variants, with Dr. Juan Pablo Ochoa suggesting that “calling them intermediate-effect variants is appropriate. They could also be called ‘low-penetrance variants’. The term risk allele (or variant) or risk factor could be used if the association is less pronounced, as is the case with some variants near the frequency of polymorphisms.”


Regarding their importance, he assures that these variants “will be important in hypertrophic cardiomyopathy, explaining a high proportion of sporadic or late-onset cases, with low familial aggregation. They have been very important in long QT syndrome, especially in the acquired form, where many variants are considered risk factors for the development of this phenotype. It will be necessary to explore them in other inherited heart diseases to see if the observed pattern is replicated.”


This introduces a problem with the pathogenicity classification criteria of the ACMG (American College of Medical Genetics and Genomics) guidelines. These guidelines were primarily developed for genetic variants with a Mendelian or monogenic pattern applied to classical genetics. “The criteria used do not work for these variants, as they fall through and end up categorizing them as benign variants or of uncertain significance when they do have an effect. The guidelines mention ‘risk factors’ where these variants could be included. But definitely, the criteria to call a variant this way should be reviewed.”


Therefore, it is not yet clear what approach healthcare professionals should take upon finding one of these intermediate-effect variants. “The easy answer is that if no other variant is present in the study, it can be considered negative, as no predictive variant has been identified. Therefore, clinical cascade screening of first-degree relatives should proceed, as indicated in the guidelines, that is, clinical follow-up of first-degree relatives with complementary studies at regular intervals,” says Dr. Ochoa.


Dr. Jesús Piqueras emphasizes that to determine the pathogenicity of a genetic variant, a key aspect is examining familial cosegregation along with the observed phenotype. Cardiological study methods are varied, and when aiming to establish a causal link between a gene and heart disease, it is crucial to employ the most effective tools to ascertain the presence, absence, severity, or type of the heart disease.


“In this regard, the presented work involves a comprehensive study of patients and the majority of their relatives, utilizing, for instance, cardiac resonance. Additionally, the postmortem examination of one of the index cases stands out in this study, where the analysis, following macroscopic and histopathological examination, was concluded with a molecular autopsy. This autopsy revealed that both FHOD3 alleles carried the same studied variant. In cases of sudden cardiac death among the young, molecular autopsy and genetic analysis are pivotal for elucidating the etiology and broadening our current understanding, as demonstrated by the family discussed in the manuscript,” adds Dr. Piqueras.


Currently, there is no definitive guideline for including these genetic variants in screening protocols for unaffected first-degree relatives, since the best approach remains uncertain. “From my perspective, it might become feasible in the future to include these variants in cases where no other obvious cause of disease exists. Non-carriers could potentially be exempt from further follow-up (similar to the approach with monogenic variants), while carriers might be monitored at less frequent intervals due to the significantly lower penetrance compared to other variants. However, this hypothesis requires validation through clinical trials before it can be implemented in clinical practice,” concludes Dr. Juan Pablo Ochoa.



Key findings of this collaborative study

More than seven centers in Spain and Ireland participated in the study, showcasing how inter-center collaboration is crucial for genetic research. Dr. Jesús Piqueras Flores points out, “Though there are limitations in terms of how much data we can extract from specific families or patients, when we consolidate knowledge about a gene and its behavior across multiple individuals and families, our understanding increases exponentially. This makes our findings significantly valuable, particularly in studies like ours that explore the roles and significance of new genes in specific diseases.”


Following the 2018 multicenter study led by Juan Pablo Ochoa and published in the Journal of the American College of Cardiology (JACC), the role of FHOD3 in HCM among heterozygous carriers was clearly show, attributing approximately 2% of HCM cases to this gene. However, the phenotype observed in this study was not severe, and pathogenic variants were found within a specific cluster.


“In this new work, we identified a variant within the same cluster, reinforcing the critical role of this region in the protein’s function and the gene’s pathogenicity. Additionally, we established the biological plausibility of the involvement of FHOD3 in HCM. Homozygotes displayed a significantly more severe phenotype than heterozygotes. Our results highlight the necessity of including this gene in HCM panels. The variant we studied has a non-negligible population frequency, and in heterozygotes it is often considered more a risk factor than a clearly pathogenic variant. Given its frequency in HCM, the likelihood of encountering homozygotes is not as low as one might initially think,” concludes Dr. Piqueras.


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