title: Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.
abstract: Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of "CTD-negative" families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3-5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Markunas
authors.forename: Karen
authors.initials: K
authors.lastname: Soldano
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Dunlap
authors.forename: Heidi
authors.initials: H
authors.lastname: Cope
authors.forename: Edgar
authors.initials: E
authors.lastname: Asiimwe
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Stajich
authors.forename: David
authors.initials: D
authors.lastname: Enterline
authors.forename: Gerald
authors.initials: G
authors.lastname: Grant
authors.forename: Herbert
authors.initials: H
authors.lastname: Fuchs
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: Allison E
authors.initials: AE
authors.lastname: Ashley-Koch
mesh_terms: D001139:Arnold-Chiari Malformation / Q000235:genetics*; D020090:Chromosome Segregation / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics*; D060005:Genotyping Techniques; D055451:Growth Differentiation Factor 3 / Q000235:genetics; D055431:Growth Differentiation Factor 6 / Q000235:genetics; D006801:Humans; D007714:Klippel-Feil Syndrome / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: C525974:GDF3 protein, human; C525906:GDF6 protein, human; D055451:Growth Differentiation Factor 3; D055431:Growth Differentiation Factor 6