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.