Mapping a Mendelian form of intracranial aneurysm to 1p34.3-p36.13.
The identification of pathways that underlie common disease has been greatly impacted by the study of rare families that segregate single genes with large effect. Intracranial aneurysm is a common neurological problem; the rupture of these aneurysms constitutes a frequently catastrophic neurologic event. The pathogenesis of these aneurysms is largely unknown, although genetic and environmental factors are believed to play a role. Previous genomewide studies in affected relative pairs have suggested linkage to several loci, but underlying genes have not been identified. We have identified a large kindred that segregates nonsyndromic intracranial aneurysm as a dominant trait with high penetrance. Genomewide analysis of linkage was performed using a two-stage approach: an analysis of ~10,000 single-nucleotide polymorphisms in the 6 living affected subjects, followed by the genotyping of simple tandem repeats across resulting candidate intervals in all 23 kindred members. Analysis revealed significant linkage to a single locus, with a LOD score of 4.2 at 1p34.3-p36.13 under a dominant model with high penetrance. These findings identify a Mendelian form of intracranial aneurysm and map the location of the underlying disease locus.
Nahed
Brian V
BV
Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Seker
Askin
A
Guclu
Bulent
B
Ozturk
Ali K
AK
Finberg
Karin
K
Hawkins
Abigail A
AA
DiLuna
Michael L
ML
State
Matthew
M
Lifton
Richard P
RP
Gunel
Murat
M
D000328:Adult; D000367:Age Factors; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide