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

Abstract

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.

The Genetics of Cervical Artery Dissection

“…56 A third study performed a whole genome linkage analysis and identified 2 suggestive candidate loci on chromosomes 15q24 and 10q26 with logarithm of odds scores of 2.1 and 1.9 in one family. 49 The same regions were, however, excluded in 2 other families, suggesting locus heterogeneity of the connective tissue phenotype. 49 …”

“…49 The same regions were, however, excluded in 2 other families, suggesting locus heterogeneity of the connective tissue phenotype. 49 …”

“…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.…”

Familial Cervical Artery Dissections

“…12 A candidate locus on chromosome 15q2 was recently found by genetic linkage analysis in 1 large family with connective tissue alterations associated with CAD. 13 That study of 3 families with sporadic CAD patients analyzed the segregation of the connective tissue phenotype as an intermediate marker. A segregation analysis of subjects affected with CAD was virtually impossible because familial cases of CAD were too rare.…”

Association between Single Nucleotide Polymorphisms in the Lysyl Oxidase-Like 1 Gene and Spontaneous Cervical Artery Dissection

“…In some families the connective tissue abnormalities, but not sCAD as such, were present in multiple family members compatible with autosomal dominant inheritance [4]. In one of these families suggestive linkage between connective tissue abnormalities and genetic markers on chromosome 15q24 has recently been demonstrated [5]. The candidate region comprises the lysyl oxidase-like 1 ( LOXL1 ) gene which is an excellent functional candidate [[5], and http://genome.ucsc.edu/].…”