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.
Highlights
Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull and occurs with an estimated prevalence of less than one percent in the United States [1,2]
Additional Single nucleotide polymorphism (SNP) were excluded with Mendelian errors in .4% families (N = 220), minor allele frequency (MAF),0.05 (N = 66355), Hardy-Weinberg equilibrium (HWE) p,0.001 (N = 275), identical physical location (Human genome build GRCh37/hg19; N = 2), no genetic distance available from deCODE (N = 948), call present in only batch 1 (N = 2445), call present in only batch 2 (N = 2991), and identical genetic position
While we presented linkage results within the subsets of both connective tissue disorder (CTD)-positive and CTD-negative families, the focus of the current paper has been on the CTD-negative families as these are thought to represent more ‘‘classical’’ CMI due to cranial constriction and resulted in the identification of the only genomic region with a maximum logarithm of the odds (LOD) score exceeding 3
Summary
Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull and occurs with an estimated prevalence of less than one percent in the United States [1,2]. Multiple mechanisms have been proposed for cerebellar tonsillar herniation, including cranial constriction, cranial settling, spinal cord tethering, intracranial hypertension, and intraspinal hypotension [6], ‘‘classical’’ CMI is generally hypothesized to occur through the ‘‘cranial constriction’’ mechanism. ‘‘classical’’ CMI is thought to be caused by an underdeveloped occipital bone, resulting in a posterior fossa (PF) which is too small and shallow to accommodate the normal sized cerebellum [7,8]. CMI patients diagnosed with CTDs may represent a distinct class of patients that can be grouped under the ‘‘cranial settling’’ mechanism where both the occipital bone and posterior cranial fossa volume are normal in size but occipitoatlantoaxial joint instability exists [6]
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