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Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.

Publication ,  Journal Article
Markunas, CA; Enterline, DS; Dunlap, K; Soldano, K; Cope, H; Stajich, J; Grant, G; Fuchs, H; Gregory, SG; Ashley-Koch, AE
Published in: Ann Hum Genet
January 2014

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease-relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on Chromosomes 1 (LOD = 3.07, p = 3 × 10(-3) ) and 22 (LOD = 3.45, p = 6 × 10(-5) ) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies.

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Published In

Ann Hum Genet

DOI

EISSN

1469-1809

Publication Date

January 2014

Volume

78

Issue

1

Start / End Page

1 / 12

Location

England

Related Subject Headings

  • Young Adult
  • Quantitative Trait, Heritable
  • Principal Component Analysis
  • Middle Aged
  • Male
  • Humans
  • Genetics & Heredity
  • Genetic Linkage
  • Female
  • Endophenotypes
 

Citation

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Markunas, C. A., Enterline, D. S., Dunlap, K., Soldano, K., Cope, H., Stajich, J., … Ashley-Koch, A. E. (2014). Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation. Ann Hum Genet, 78(1), 1–12. https://doi.org/10.1111/ahg.12041
Markunas, Christina A., David S. Enterline, Kaitlyn Dunlap, Karen Soldano, Heidi Cope, Jeffrey Stajich, Gerald Grant, Herbert Fuchs, Simon G. Gregory, and Allison E. Ashley-Koch. “Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.Ann Hum Genet 78, no. 1 (January 2014): 1–12. https://doi.org/10.1111/ahg.12041.
Markunas CA, Enterline DS, Dunlap K, Soldano K, Cope H, Stajich J, et al. Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation. Ann Hum Genet. 2014 Jan;78(1):1–12.
Markunas, Christina A., et al. “Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.Ann Hum Genet, vol. 78, no. 1, Jan. 2014, pp. 1–12. Pubmed, doi:10.1111/ahg.12041.
Markunas CA, Enterline DS, Dunlap K, Soldano K, Cope H, Stajich J, Grant G, Fuchs H, Gregory SG, Ashley-Koch AE. Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation. Ann Hum Genet. 2014 Jan;78(1):1–12.
Journal cover image

Published In

Ann Hum Genet

DOI

EISSN

1469-1809

Publication Date

January 2014

Volume

78

Issue

1

Start / End Page

1 / 12

Location

England

Related Subject Headings

  • Young Adult
  • Quantitative Trait, Heritable
  • Principal Component Analysis
  • Middle Aged
  • Male
  • Humans
  • Genetics & Heredity
  • Genetic Linkage
  • Female
  • Endophenotypes