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Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort
Lisa M van den Bersselaar1, Judith M A Verhagen1, Jos A Bekkers2
1Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Insights
Pathogenic variants in the ACTA2 gene significantly increase the risk of thoracic aortic aneurysms and dissections. Early recognition is crucial, as aortic events can occur even with normal aortic diameters.
Area of Science:
- Genetics
- Cardiology
- Vascular Biology
Background:
- Pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene are linked to a high risk of thoracic aortic aneurysms and aortic dissections.
- ACTA2-related vasculopathies represent a significant clinical challenge due to their potential for severe cardiovascular events.
Purpose of the Study:
- To elucidate the clinical outcomes and characteristics of individuals with ACTA2-related vasculopathies.
- To identify risk factors associated with aortic events in patients carrying P/LP ACTA2 variants.
Main Methods:
- A retrospective multicenter study involving index patients and relatives with P/LP ACTA2 variants.
- Data collection via standardized questionnaires and medical record review.
Main Results:
- The study included 49 individuals from 28 families, with 20 different ACTA2 variants identified.
- Aortic events occurred in 65% of participants, with male sex and hypertension being significant risk factors.
- Aortic dissections were observed even in individuals with aortic diameters <45 mm, with a mean age of first event at 49.0 years.
Conclusions:
- P/LP ACTA2 variants are strongly associated with an increased risk of aortic events and age-related penetrance.
- Early diagnosis and awareness of ACTA2-related vasculopathies are critical for timely intervention.
- Healthcare providers should consider the risk of aortic dissection even in patients with normal aortic dimensions.
Purpose:
Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies.
Methods:
Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire.
Results:
A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively.
Conclusion:
P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.
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