title: Phenotypic definition of Chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15.
abstract: Chiari type I malformation (CMI; OMIM 118420) is narrowly defined when the tonsils of the cerebellum extend below the foramen magnum, leading to a variety of neurological symptoms. It is widely thought that a small posterior fossa (PF) volume, relative to the total cranial volume leads to a cramped cerebellum and herniation of the tonsils into the top of the spinal column. In a collection of magnetic resonance imagings (MRIs) from affected individuals and their family members, we measured correlations between ten cranial morphologies and estimated their heritability in these families. Correlations between bones delineating the PF and significant heritability of PF volume (0.955, P = 0.003) support the cramped PF theory and a genetic basis for this condition. In a collection of 23 families with 71 affected individuals, we performed a genome wide linkage screen of over 10,000 SNPs across the genome to identify regions of linkage to CMI. Two-point LOD scores on chromosome 15 reached 3.3 and multipoint scores in this region identified a 13 cM region with LOD scores over 1 (15q21.1-22.3). This region contains a biologically plausible gene for CMI, fibrillin-1, which is a major gene in Marfan syndrome and has been linked to Shprintzen-Goldberg syndrome, of which CMI is a distinguishing characteristic. Multipoint LOD scores on chromosome 9 maximized at 3.05, identifying a 40 cM region with LOD scores over 1 (9q21.33-33.1) and a tighter region with multipoint LOD scores over 2 that was only 8.5 cM. This linkage evidence supports a genetic role in Chiari malformation and justifies further exploration with fine mapping and investigation of candidate genes in these regions.
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Abee L
authors.initials: AL
authors.lastname: Boyles
authors.forename: David S
authors.initials: DS
authors.lastname: Enterline
authors.forename: Preston H
authors.initials: PH
authors.lastname: Hammock
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Siegel
authors.forename: Susan H
authors.initials: SH
authors.lastname: Slifer
authors.forename: Lorraine
authors.initials: L
authors.lastname: Mehltretter
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.forename: Diane
authors.initials: D
authors.lastname: Hu-Lince
authors.forename: Dietrich
authors.initials: D
authors.lastname: Stephan
authors.forename: Ulrich
authors.initials: U
authors.lastname: Batzdorf
authors.forename: Edward
authors.initials: E
authors.lastname: Benzel
authors.forename: Richard
authors.initials: R
authors.lastname: Ellenbogen
authors.forename: Barth A
authors.initials: BA
authors.lastname: Green
authors.forename: Roger
authors.initials: R
authors.lastname: Kula
authors.forename: Arnold
authors.initials: A
authors.lastname: Menezes
authors.forename: Diane
authors.initials: D
authors.lastname: Mueller
authors.forename: John J
authors.initials: JJ
authors.lastname: Oro'
authors.forename: Bermans J
authors.initials: BJ
authors.lastname: Iskandar
authors.forename: Timothy M
authors.initials: TM
authors.lastname: George
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Milhorat
authors.forename: Marcy C
authors.initials: MC
authors.lastname: Speer
mesh_terms: D001139:Arnold-Chiari Malformation / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003388:Cranial Fossa, Posterior / Q000002:abnormalities; D005260:Female; D005539:Foramen Magnum / Q000002:abnormalities; D008040:Genetic Linkage; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008297:Male; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide