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Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.

Publication ,  Journal Article
Markunas, CA; Soldano, K; Dunlap, K; Cope, H; Asiimwe, E; Stajich, J; Enterline, D; Grant, G; Fuchs, H; Gregory, SG; Ashley-Koch, AE
Published in: PLoS One
2013

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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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

4

Start / End Page

e61521

Location

United States

Related Subject Headings

  • Sequence Analysis, DNA
  • Pedigree
  • Mutation, Missense
  • Molecular Sequence Data
  • Male
  • Lod Score
  • Klippel-Feil Syndrome
  • Humans
  • Growth Differentiation Factor 6
  • Growth Differentiation Factor 3
 

Citation

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Chicago
ICMJE
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Markunas, C. A., Soldano, K., Dunlap, K., Cope, H., Asiimwe, E., Stajich, J., … Ashley-Koch, A. 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), e61521. https://doi.org/10.1371/journal.pone.0061521
Markunas, Christina A., Karen Soldano, Kaitlyn Dunlap, Heidi Cope, Edgar Asiimwe, Jeffrey Stajich, David Enterline, et al. “Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.PLoS One 8, no. 4 (2013): e61521. https://doi.org/10.1371/journal.pone.0061521.
Markunas CA, Soldano K, Dunlap K, Cope H, Asiimwe E, Stajich J, et al. Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates. PLoS One. 2013;8(4):e61521.
Markunas, Christina A., et al. “Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.PLoS One, vol. 8, no. 4, 2013, p. e61521. Pubmed, doi:10.1371/journal.pone.0061521.
Markunas CA, Soldano K, Dunlap K, Cope H, Asiimwe E, Stajich J, Enterline D, Grant G, Fuchs H, Gregory SG, Ashley-Koch AE. Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates. PLoS One. 2013;8(4):e61521.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

4

Start / End Page

e61521

Location

United States

Related Subject Headings

  • Sequence Analysis, DNA
  • Pedigree
  • Mutation, Missense
  • Molecular Sequence Data
  • Male
  • Lod Score
  • Klippel-Feil Syndrome
  • Humans
  • Growth Differentiation Factor 6
  • Growth Differentiation Factor 3