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.

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Citation

Published Version (Please cite this version)

10.1371/journal.pone.0061521

Publication Info

Markunas, Christina A, Karen Soldano, Kaitlyn Dunlap, Heidi Cope, Edgar Asiimwe, Jeffrey Stajich, David Enterline, Gerald Grant, et al. (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). p. e61521. 10.1371/journal.pone.0061521 Retrieved from https://hdl.handle.net/10161/25906.

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Scholars@Duke

Enterline

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 & Kyphoplasty, Spine Pain Management

Grant

Gerald Arthur Grant

Allan H. Friedman Distinguished Professor of Neurosurgery
Fuchs

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.

Gregory

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 diseases using genetic, genomic, and epigenetic approaches. Dr. Gregory’s primary areas of research involve understanding the molecular processes associated with disease development and progression in brain tumors and Alzheimer’s disease, novel drug induced white matter injury repair in multiple sclerosis, and social and behavioral response to oxytocin treatment animal models of autism. 

He is broadly regarded across Duke as a leader in the development of novel single cell and spatial molecular technologies towards understanding the pathogenic mechanisms of disease development. Dr. Gregory is also the Section Chair of Genomics and Epigenetics at the DMPI and Director of the Duke Center of Autoimmunity and MS in the Department of Neurology.

Ashley-Koch

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.


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