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Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections
D M Milewicz1, H Chen, E S Park
1Department of Internal Medicine, University of Texas-Houston Medical School, 77030, USA.
Abstract:
Autosomal dominant inheritance of thoracic aortic aneurysms and dissections occurs in subjects with Marfan syndrome, which results from mutations in the FBN1 gene on chromosome 15. A second chromosomal locus on 3p24-25 has been identified for a Marfan-like condition with thoracic aortic aneurysms. We describe here 6 families with multiple members with thoracic aortic aneurysms and dissections in the absence of the ocular and skeletal complications of Marfan syndrome. Medical records and autopsy reports on affected subjects in families with multiple members with thoracic aortic aneurysms and dissections were reviewed. Subjects in these families at risk for developing aortic disease underwent echocardiography to evaluate the aorta. The pattern of inheritance of thoracic aortic aneurysms and dissections was autosomal dominant in these families. Most affected subjects presented with aortic root dilatation or acute type I dissection, but the age of onset of disease was variable and there was decreased penetrance of the disorder. In 2 of the families, the syndrome was not linked to FBN1 or 3p24-25. Familial thoracic aortic aneurysm and dissection is an autosomal dominant condition with marked variability in the age of onset of aortic disease and decreased penetrance, making identification of affected subjects difficult. This condition is not due to mutations in the FBN1 gene or the unidentified gene on 3p24-25.
Insights
Familial thoracic aortic aneurysm and dissection (TAAD) is an autosomal dominant condition. This TAAD form is not caused by FBN1 gene mutations or the previously identified 3p24-25 locus.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Medical Research
Background:
- Marfan syndrome, caused by FBN1 gene mutations, presents with autosomal dominant inheritance of thoracic aortic aneurysms and dissections (TAAD).
- A separate locus on chromosome 3p24-25 is associated with a Marfan-like condition also causing TAAD.
- Identifying the genetic basis of familial TAAD is crucial for understanding disease mechanisms and inheritance patterns.
Observation:
- Six families with multiple affected members exhibiting TAAD, but lacking Marfan syndrome's characteristic ocular and skeletal features, were studied.
- Medical records, autopsy reports, and echocardiography were used to evaluate affected individuals and assess aortic health in at-risk family members.
- The inheritance pattern of TAAD in these families was confirmed as autosomal dominant.
Findings:
- Affected individuals commonly presented with aortic root dilatation or acute type I dissection.
- The age of disease onset in these families was variable, and the condition exhibited decreased penetrance.
- Genetic analysis revealed that the TAAD in two of the studied families was not linked to the FBN1 gene or the 3p24-25 locus.
Implications:
- Familial TAAD is an autosomal dominant disorder with significant variability in disease onset and reduced penetrance, complicating subject identification.
- The genetic cause of TAAD in these families remains unidentified, suggesting novel genetic factors may be involved.
- Further research is needed to elucidate the genetic underpinnings of this distinct form of familial thoracic aortic disease.