Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome

Errichiello, Edoardo; Malara, Alessandro; Grimod, Gianluca; Avolio, Luigi; Balduini, Alessandra; Zuffardi, Orsetta

doi:10.1016/j.ejmg.2020.104099

Cited by 3 publications

(5 citation statements)

References 57 publications

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“…Interestingly, 3 of these variants reside within the collagen triple helix domain, where 63% of HGMD reported disease‐associated missense alleles are located. 29 , 30 …”

Section: Resultsmentioning

confidence: 99%

Contributions of Germline and Somatic Mosaic Genetics to Thoracic Aortic Aneurysms in Nonsyndromic Individuals

Chen,

Deng,

Yamada

et al. 2024

JAHA

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Background Thoracic aortic aneurysm (TAA) is associated with significant morbidity and mortality. Although individuals with family histories of TAA often undergo clinical molecular genetic testing, adults with nonsyndromic TAA are not typically evaluated for genetic causes. We sought to understand the genetic contribution of both germline and somatic mosaic variants in a cohort of adult individuals with nonsyndromic TAA at a single center. Methods and Results One hundred eighty‐one consecutive patients <60 years who presented with nonsyndromic TAA at the Massachusetts General Hospital underwent deep (>500×) targeted sequencing across 114 candidate genes associated with TAA and its related functional pathways. Samples from 354 age‐ and sex‐matched individuals without TAA were also sequenced, with a 2:1 matching. We found significant enrichments for germline (odds ratio [OR], 2.44, P =4.6×10 −6 [95% CI, 1.67–3.58]) and also somatic mosaic variants (OR, 4.71, P =0.026 [95% CI, 1.20–18.43]) between individuals with and without TAA. Likely genetic causes were present in 24% with nonsyndromic TAA, of which 21% arose from germline variants and 3% from somatic mosaic alleles. The 3 most frequently mutated genes in our cohort were FLNA (encoding Filamin A), NOTCH3 (encoding Notch receptor 3), and FBN1 (encoding Fibrillin‐1). There was increased frequency of both missense and loss of function variants in TAA individuals. Conclusions Likely contributory dominant acting genetic variants were found in almost one quarter of nonsyndromic adults with TAA. Our findings suggest a more extensive genetic architecture to TAA than expected and that genetic testing may improve the care and clinical management of adults with nonsyndromic TAA.

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“…Interestingly, 3 of these variants reside within the collagen triple helix domain, where 63% of HGMD reported disease‐associated missense alleles are located. 29 , 30 …”

Section: Resultsmentioning

confidence: 99%

Contributions of Germline and Somatic Mosaic Genetics to Thoracic Aortic Aneurysms in Nonsyndromic Individuals

Chen,

Deng,

Yamada

et al. 2024

JAHA

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“…23,24 A recent report of intracranial aneurysms in a patient with compound heterozygous COL5A1 variants, suggested a threshold for the vascular manifestation in cEDS patients where the combination of variants in this genes increases the penetrance of vascular findings. 24 In addition, there have been reports of families harboring different COL5A1 variants who presented with fatal vascular events in an age range of 11-43 years, despite having very mild signs of EDS. 23 Patients with EDS usually undergo cardiac echocardiography as a part of the additional workup after initial diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…One of the EDS subtypes frequently reported to be associated with critical aneurysms is cEDS, caused by heterozygous mutations in COL5A1 or COL5A2 , encoding type V collagen 23,24 . A recent report of intracranial aneurysms in a patient with compound heterozygous COL5A1 variants, suggested a threshold for the vascular manifestation in cEDS patients where the combination of variants in this genes increases the penetrance of vascular findings 24 . In addition, there have been reports of families harboring different COL5A1 variants who presented with fatal vascular events in an age range of 11–43 years, despite having very mild signs of EDS 23 …”

Section: Discussionmentioning

confidence: 99%

Vascular aneurysms in Ehlers‐Danlos syndrome subtypes: A systematic review

et al. 2022

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Aneurysmal lesions are commonly seen in Ehlers‐Danlos Syndrome (EDS). To better identify the regional and vessel‐specific spectrum of aneurysms in different subtypes of EDS, we performed a systematic review. We searched Medline for relevant studies from 1963 to April 2022. Studies providing a report of any EDS subtype by genetic diagnosis, histologic analysis, or clinical criteria were included. A total of 448 patients from 220 studies were included. 720 vessel‐specific aneurysms were reported: 386 in the abdominopelvic area, 165 in the intracranial region, 98 in the thorax, 2 in the extremities, and 6 in the venous system. In 27 out of the 65 patients with ruptured aneurysms, the ruptured aneurysm was the initial presentation. Multiple aneurysms were present in 163 out of 249 patients who had been systematically evaluated for other locations of aneurysms. The head and neck and abdominopelvic regions are two potential foci for aneurysm formation in patients with EDS. The aneurysm development in EDS is not confined to arteries; the venous system and cardiac septa may also be affected. Many patients develop multiple aneurysms, either at the time of the initial presentation or throughout their lifetime and aneurysm formation or rupture may be the first presentation of EDS.

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“…Cells 2024, 13, x FOR PEER REVIEW 6 of 23 factors determining weakened collagen matrix and a predisposition to AAA [64,65]. Mutations in the fibrillin-1 gene (FBN1) are the causative factor for Marfan syndrome (MFS), a disorder of connective tissue morphology of which one of the consequences is a fragmentation of elastin fibers, which may be a reason for MFS-related aortic aneurysm [66].…”

Section: Abdominal Aorta Aneurysm-cellular Physiology and Pathophysio...mentioning

confidence: 99%

“…The degeneration of ECM component shows regional heterogeneity on the circumference of the aneurysm [63]. Genetic variants of synthesize collagen are also crucial for the mechanical properties of the aorta; heterozygous mutations in COL3A1 or COL5A1 are reported as factors determining weakened collagen matrix and a predisposition to AAA [64,65]. Mutations in the fibrillin-1 gene (FBN1) are the causative factor for Marfan syndrome (MFS), a disorder of connective tissue morphology of which one of the consequences is a fragmentation of elastin fibers, which may be a reason for MFS-related aortic aneurysm [66].…”

Section: Abdominal Aorta Aneurysm-cellular Physiology and Pathophysio...mentioning

confidence: 99%

Cellular, Molecular and Clinical Aspects of Aortic Aneurysm—Vascular Physiology and Pathophysiology

Domagała,

Data,

Szyller

et al. 2024

Cells

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A disturbance of the structure of the aortic wall results in the formation of aortic aneurysm, which is characterized by a significant bulge on the vessel surface that may have consequences, such as distention and finally rupture. Abdominal aortic aneurysm (AAA) is a major pathological condition because it affects approximately 8% of elderly men and 1.5% of elderly women. The pathogenesis of AAA involves multiple interlocking mechanisms, including inflammation, immune cell activation, protein degradation and cellular malalignments. The expression of inflammatory factors, such as cytokines and chemokines, induce the infiltration of inflammatory cells into the wall of the aorta, including macrophages, natural killer cells (NK cells) and T and B lymphocytes. Protein degradation occurs with a high expression not only of matrix metalloproteinases (MMPs) but also of neutrophil gelatinase-associated lipocalin (NGAL), interferon gamma (IFN-γ) and chymases. The loss of extracellular matrix (ECM) due to cell apoptosis and phenotype switching reduces tissue density and may contribute to AAA. It is important to consider the key mechanisms of initiating and promoting AAA to achieve better preventative and therapeutic outcomes.

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Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome

Cited by 3 publications

References 57 publications

Contributions of Germline and Somatic Mosaic Genetics to Thoracic Aortic Aneurysms in Nonsyndromic Individuals

Contributions of Germline and Somatic Mosaic Genetics to Thoracic Aortic Aneurysms in Nonsyndromic Individuals

Vascular aneurysms in Ehlers‐Danlos syndrome subtypes: A systematic review

Cellular, Molecular and Clinical Aspects of Aortic Aneurysm—Vascular Physiology and Pathophysiology

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