Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.
Date
2013-01
Editor
Krahe, Ralf
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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.
Type
Journal articleSubject
HumansKlippel-Feil Syndrome
Arnold-Chiari Malformation
Genetic Predisposition to Disease
Pedigree
Sequence Analysis, DNA
Chromosome Segregation
Lod Score
Mutation, Missense
Genome, Human
Molecular Sequence Data
Female
Male
Growth Differentiation Factor 6
Growth Differentiation Factor 3
Genetic Association Studies
Genetic Linkage
Genotyping Techniques
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https://hdl.handle.net/10161/25906Published Version (Please cite this version)
10.1371/journal.pone.0061521Publication Info
Markunas, Christina A; Soldano, Karen; Dunlap, Kaitlyn; Cope, Heidi; Asiimwe, Edgar;
Stajich, Jeffrey; ... Ashley-Koch, Allison E (2013). Stratified whole genome linkage analysis of Chiari type I malformation implicates
known Klippel-Feil syndrome genes as putative disease candidates. PloS one, 8(4). pp. e61521. 10.1371/journal.pone.0061521. Retrieved from https://hdl.handle.net/10161/25906.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Allison Elizabeth Ashley-Koch
Professor in Medicine
One of my major research foci is in the genetic basis of psychiatric and neurological
disorders. I am currently involved in studies to dissect the genetic etiology of
attention deficit hyperactivity disorder (ADHD), autism, chiari type I malformations,
essential tremor, and neural tube defects. Additional research foci include genetic
modifiers of sickle cell disease, and genetic contributions to birth outcomes, particularly
among African American women.
David Scott Enterline
Consulting Associate in the Department of Radiology
Neuroradiology and Interventional Neuroradiology Modalities Improvements: MRI, MDCT,
CT Angiography, Angiography Topics: Adult Neuroradiology - Vascular Diseases, Brain
Tumors, Spine Disease, Pediatric Neuroradiology - Brain Tumors, Congenital & Genetic
Diseases, Chiari I malformation, Seizure Disorders Interventional Neuroradiology
- Carotid Stents, Endovascular treatment of cerebral aneurysms and AVMs, Vertebroplasty
&am
Herbert Edgar Fuchs
Professor of Neurosurgery
Clinical neuro-oncology research including collaborations studying molecular genetics
of childhood brain tumors. Potential role of the free electron laser in surgery
of pediatric brain tumors. Current work includes animal models with human brain tumor
xenografts in preclinical studies. Collaboration with the neurooncology laboratory
of Dr. Darell Bigner in preclinical studies of new therapeutic agents.
Gerald Arthur Grant
Allan H. Friedman Distinguished Professor of Neurosurgery
Simon Gray Gregory
Professor in Neurosurgery
Dr. Gregory is a tenured Professor and Director of the Brain Tumor Omics Program (BTOP)
in the Duke Department of Neurosurgery, the Vice Chair of Research in the Department
of Neurology, and Director of the Molecular Genomics Core at the Duke Molecular Physiology
Institute.
As a neurogenomicist, Dr. Gregory applies the experience gained from leading the sequencing
of chromosome 1 for the Human Genome Project to elucidating the mechanisms underlying
multi-factorial
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