Abdominal Aortic Aneurysm in Males as the Predominant Presentation of Vascular EDS in a Family With a Novel COL3A1 Variant
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Vascular Ehler Danlos Syndrome (vEDS) is a heritable connective tissue disorder characterized by arterial fragility and increased risk of arterial aneurysms and/or dissections as well as hollow organ tissue fragility. vEDS is caused by pathogenic variants in COL3A1, encoding the alpha-1 chain of collagen type III. vEDS was thought to be universally associated with arterial events by mid-early adulthood. However, individuals with milder presentations are increasingly being recognized. We present a large family with a novel likely pathogenic variant in COL3A1 in whom most male variant carriers present with an abdominal aortic aneurysm (AAA).
Methods:
Clinical and molecular data for a family was collected including history focused on connective tissue disorders, cardiovascular risk factors defined as smoking, hypertension, and dyslipidemia, a 5-generational family history, focused physical examination, head-to-pelvis vascular imaging, and echocardiogram.
Results:
The proband, a 73-year-old female, was referred to the genetics clinic after a type A aortic dissection requiring surgical repair. Initially, aortitis was suspected and treated with several months of high-dose prednisone based on a thickened aortic wall without dissection flap on imaging and elevated inflammatory markers in the context of bacteremia. Repeat CT angiography revealed a type A aortic dissection and urgent surgical repair was arranged. Aortic biopsy was negative for active or chronic features of aortitis. It was concluded that the previous imaging findings represented an intramural hematoma which progressed to a dissection. Head-to-pelvis imaging showed multiple abdominal aneurysms and tortuosity in multiple vascular beds. An 11-gene heritable thoracic aortic aneurysm and dissection panel identified a COL3A1 likely pathogenic c.511G>A (p.Gly171Ser) variant which substitutes the second last glycine of the triple helix. It is absent from gnomAD v4.1 and is reported twice as likely pathogenic in ClinVar.
Eight additional family members (4 males aged 55-80 and 4 females aged 36-63) were found to share this variant and 2 males to be obligate carriers. Four of the 6 males have a AAA and 1 has an ectatic ascending aorta; all have a history of smoking. All individuals with AAA have a first degree relative with AAA who is also a variant carrier. The proband is the only female with any arterial involvement. Other female carriers in their 60’s or late 50’s remain unaffected. There is also family history of brain aneurysms in 4 females and 1 male who have not had genetic testing.
Conclusion:
In this family with vEDS, the most common phenotype is AAA in males who all have cardiovascular risk factors. This is interesting as in most familial AAA’s no monogenic cause is identified. AAA’s are more common in males and smokers.
Our findings are consistent with previous evidence that males affected by vEDS have a more severe phenotype, higher rate of aneurysms, and lower survival than affected females. In this family, a 69-year-old male and most female variant carriers even in their 60’s remain unaffected, supporting the emerging evidence that penetrance of vEDS is lower than previously estimated.
These findings highlight the interplay of genetic modifiers and modifiable risk factors particularly with mild/low penetrance variants.
Vascular Ehler Danlos Syndrome (vEDS) is a heritable connective tissue disorder characterized by arterial fragility and increased risk of arterial aneurysms and/or dissections as well as hollow organ tissue fragility. vEDS is caused by pathogenic variants in COL3A1, encoding the alpha-1 chain of collagen type III. vEDS was thought to be universally associated with arterial events by mid-early adulthood. However, individuals with milder presentations are increasingly being recognized. We present a large family with a novel likely pathogenic variant in COL3A1 in whom most male variant carriers present with an abdominal aortic aneurysm (AAA).
Methods:
Clinical and molecular data for a family was collected including history focused on connective tissue disorders, cardiovascular risk factors defined as smoking, hypertension, and dyslipidemia, a 5-generational family history, focused physical examination, head-to-pelvis vascular imaging, and echocardiogram.
Results:
The proband, a 73-year-old female, was referred to the genetics clinic after a type A aortic dissection requiring surgical repair. Initially, aortitis was suspected and treated with several months of high-dose prednisone based on a thickened aortic wall without dissection flap on imaging and elevated inflammatory markers in the context of bacteremia. Repeat CT angiography revealed a type A aortic dissection and urgent surgical repair was arranged. Aortic biopsy was negative for active or chronic features of aortitis. It was concluded that the previous imaging findings represented an intramural hematoma which progressed to a dissection. Head-to-pelvis imaging showed multiple abdominal aneurysms and tortuosity in multiple vascular beds. An 11-gene heritable thoracic aortic aneurysm and dissection panel identified a COL3A1 likely pathogenic c.511G>A (p.Gly171Ser) variant which substitutes the second last glycine of the triple helix. It is absent from gnomAD v4.1 and is reported twice as likely pathogenic in ClinVar.
Eight additional family members (4 males aged 55-80 and 4 females aged 36-63) were found to share this variant and 2 males to be obligate carriers. Four of the 6 males have a AAA and 1 has an ectatic ascending aorta; all have a history of smoking. All individuals with AAA have a first degree relative with AAA who is also a variant carrier. The proband is the only female with any arterial involvement. Other female carriers in their 60’s or late 50’s remain unaffected. There is also family history of brain aneurysms in 4 females and 1 male who have not had genetic testing.
Conclusion:
In this family with vEDS, the most common phenotype is AAA in males who all have cardiovascular risk factors. This is interesting as in most familial AAA’s no monogenic cause is identified. AAA’s are more common in males and smokers.
Our findings are consistent with previous evidence that males affected by vEDS have a more severe phenotype, higher rate of aneurysms, and lower survival than affected females. In this family, a 69-year-old male and most female variant carriers even in their 60’s remain unaffected, supporting the emerging evidence that penetrance of vEDS is lower than previously estimated.
These findings highlight the interplay of genetic modifiers and modifiable risk factors particularly with mild/low penetrance variants.