Exclusion mapping of the genetic predisposition for cervical artery dissections by linkage analysis

Grond‐Ginsbach, Caspar; Klima, Bernhard; Weber, R.; Striegel, Johannes; Fischer, Christine; Hacke, Werner; Brandt, Tobias; Haußer, Ingrid

doi:10.1002/ana.10268

Cited by 26 publications

(24 citation statements)

References 19 publications

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“…Over 50% of these subjects had connective tissue aberrations in their reticular dermis, 18,46,47 the most common pattern being composite collagen fibrils and fragmentation of elastic fibers. These abnormalities seem to be transmitted according to an autosomal-dominant pattern 48,49 without fulfilling the diagnostic criteria for known monogenic connective tissue disorders.…”

Section: Genetics Of Sporadic Cad How Important Are Genetic Factors Imentioning

confidence: 99%

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The Genetics of Cervical Artery Dissection

Debette

Markus

2009

Stroke

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Background and Purpose-The pathophysiology of cervical artery dissections (CAD), a major cause of ischemic stroke in young adults, is poorly understood. Several arguments suggest a genetic predisposition. Methods-We systematically reviewed all published data on genetic risk factors for CAD and performed a meta-analysis of association studies with the MTHFR C677T polymorphism. Results-Rarely, CAD is associated with a known monogenic connective tissue disease, mainly vascular Ehlers-Danlos syndrome. However, in the large majority of CAD cases, there is no evidence for a known monogenic disease. Several arguments, including the association of CAD with dermal connective tissue abnormalities that are inherited, suggest that genetic factors also play a role in "sporadic" CAD as part of a multifactorial predisposition. We identified 15 genetic association studies: 10 were negative and 5 reported associations of 3 genetic variants in 3 different candidate genes. Two studies reported associations with polymorphisms in ICAM-1 and COL3A1, but neither has been replicated. Three studies reported an association with the MTHFR 677TT genotype, but 3 other studies did not replicate this. A meta-analysis of these data identified an overall significant association of the MTHFR 677TT genotype with CAD (OR, 1.67; 95% CI, 1.21 to 2.31). We also identified 9 studies screening candidate genes for mutations and 4 linkage studies, yielding mostly negative results. Conclusions-Although several interesting hypotheses were generated, the majority of genetic studies in CAD have been negative until now, but they were markedly underpowered. Progress in unraveling the genetics of CAD will require the collection of DNA samples from large multicenter series. (Stroke. 2009;40:e459-e466.)

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Section: Genetics Of Sporadic Cad How Important Are Genetic Factors Imentioning

confidence: 99%

“…A first study 48 tested linkage with microsatellite markers for 43 candidates genes involved in the synthesis of extracellular matrix components in one family. Most genes were excluded with logarithm of odds scores ϽϪ2.0.…”

Section: Linkage Studiesmentioning

confidence: 99%

The Genetics of Cervical Artery Dissection

Debette

Markus

2009

Stroke

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“…10 Family C was analyzed in a previous exclusion mapping study. 9 Deep-knife skin biopsies were sampled from all 3 index patients and prepared for histology, electron microscopy and for culturing of fibroblasts as described. 8 All patients showed clear and reproducible connective tissue alterations of the same ("Ehlers Danlos syndrome-III like") 8 type.…”

Section: Methodsmentioning

confidence: 99%

“…8 The most common type of connective tissue aberrations with composite collagen fibrils and fragmentation of elastic fibers was studied previously in a small pedigree and found to be familial with an autosomal dominant pattern of inheritance. 9 In this study we present 2 additional and larger families with inherited connective tissue aberrations of the same pattern. We performed a genome-wide genetic linkage analysis to identify a susceptibility locus, responsible for the connective tissue phenotype and increasing the risk for CAD.…”

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confidence: 99%

Genetic Analysis of Familial Connective Tissue Alterations Associated With Cervical Artery Dissections Suggests Locus Heterogeneity

Wiest

Hyrenbach²,

Bambul³

et al. 2006

Stroke

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Background and Purpose— Cervical artery dissections (CAD) can be associated with connective tissue aberrations in skin biopsies. The analysis of healthy relatives of patients suggested that the connective tissue phenotype is familial with an autosomal dominant inheritance. Methods— We performed genetic linkage studies in 3 families of patients with CAD. Connective tissue phenotypes for the patients and all family members were assessed by electron microscopic study of skin biopsies. A genome-wide linkage analysis of 1 family (1 patient with 8 healthy relatives) indicated 2 candidate loci. Three genes were subsequently studied by sequence analysis. Part of the genome was also studied by linkage analysis in 2 further families. Results— The genome-wide scan in a single family suggested linkage between the hypothetical mutation causing the connective tissue phenotype and informative genetic markers on chromosome 15q24 (logarithm of the odds score: Z = +2.1). A second possible candidate locus ( Z =+1.9) was found on chromosome 10q26. Sequence analysis of 3 candidate genes in the suggestive locus (chondroitin sulfate proteoglycan4 [ CSPG4 ], lysyl oxidase-like1 [ LOXL1 ] and fibroblast growth factor receptor2 [ FGFR2 ]) did not lead to the identification of a mutation responsible for connective tissue alterations. In 2 additional smaller families the loci on chromosome 15q24 and 10q26 were excluded by linkage analysis. Conclusions— Linkage analysis of a large family with CAD-associated connective tissue alterations suggested the presence of a candidate locus on chromosome 15q2 or on chromosome 10q26. Sequence analysis did not lead to the identification of a mutated candidate gene in 1 of these loci. The study of 2 additional pedigrees indicated locus heterogeneity for the connective tissue phenotype of CAD patients.

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“…Using a linkage exclusion approach, they were able to exclude 34 different genes involved in the extracellular matrix. 10 Another study of 10 patients with cervical dissections examined the alpha2 chain of type V procollagen as a candidate gene. Two different missense mutations were detected in two patients, and a third patient had two more mutations in the alpha2 (V) chain.…”

Section: Genetic Polymorphisms and Candidate Genesmentioning

confidence: 99%

Stroke Genetics Update

Alberts

2003

Stroke

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Exclusion mapping of the genetic predisposition for cervical artery dissections by linkage analysis

Cited by 26 publications

References 19 publications

The Genetics of Cervical Artery Dissection

The Genetics of Cervical Artery Dissection

Genetic Analysis of Familial Connective Tissue Alterations Associated With Cervical Artery Dissections Suggests Locus Heterogeneity

Stroke Genetics Update

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