Phenotypic definition of chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15

Abee L. Boyles, David S. Enterline, Preston H. Hammock, Deborah G. Siegel, Susan H. Slifer, Lorraine Mehltretter, John Gilbert, Diane Hu-Lince, Dietrich Stephan, Ulrich Batzdorf, Edward Benzel, Richard Ellenbogen, Barth A Green, Roger Kula, Arnold Menezes, Diane Mueller, John J. Oro, Bermans J. Iskandar, Timothy M. George, Thomas H. Milhorat & 1 others Marcy C. Speer

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Chiari type I malformation (CMI; OMIM 118420) is narrowly defined when the tonsils of the cerebellum extend below the foramen magnum, leading to a variety of neurological symptoms. It is widely thought that a small posterior fossa (PF) volume, relative to the total cranial volume leads to a cramped cerebellum and herniation of the tonsils into the top of the spinal column. In a collection of magnetic resonance imagings (MRIs) from affected individuals and their family members, we measured correlations between ten cranial morphologies and estimated their heritability in these families. Correlations between bones delineating the PF and significant heritability of PF volume (0.955, P = 0.003) support the cramped PF theory and a genetic basis for this condition. In a collection of 23 families with 71 affected individuals, we performed a genome wide linkage screen of over 10,000 SNPs across the genome to identify regions of linkage to CMI. Two-point LOD scores on chromosome 15 reached 3.3 and multipoint scores in this region identified a 13 cM region with LOD scores over 1 (15q21.1-22.3). This region contains a biologically plausible gene for CMI, fibrillin-1, which is a major gene in Marfan syndrome and has been linked to Shprintzen-Goldberg syndrome, of which CMI is a distinguishing characteristic. Multipoint LOD scores on chromosome 9 maximized at 3.05, identifying a 40 cM region with LOD scores over 1 (9q21.33-33.1) and a tighter region with multipoint LOD scores over 2 that was only 8.5 cM. This linkage evidence supports a genetic role in Chiari malformation and justifies further exploration with fine mapping and investigation of candidate genes in these regions.

Original languageEnglish
Pages (from-to)2776-2785
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume140
Issue number24
DOIs
StatePublished - Dec 15 2006

Fingerprint

Arnold-Chiari Malformation
Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 9
Single Nucleotide Polymorphism
Palatine Tonsil
Genome
Cerebellum
Foramen Magnum
Genes
Genetic Databases
Marfan Syndrome
Spine
Magnetic Resonance Imaging
Bone and Bones

Keywords

  • Chiari type I malformation
  • Cranial morphology
  • Genome wide linkage screen

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Phenotypic definition of chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15. / Boyles, Abee L.; Enterline, David S.; Hammock, Preston H.; Siegel, Deborah G.; Slifer, Susan H.; Mehltretter, Lorraine; Gilbert, John; Hu-Lince, Diane; Stephan, Dietrich; Batzdorf, Ulrich; Benzel, Edward; Ellenbogen, Richard; Green, Barth A; Kula, Roger; Menezes, Arnold; Mueller, Diane; Oro, John J.; Iskandar, Bermans J.; George, Timothy M.; Milhorat, Thomas H.; Speer, Marcy C.

In: American Journal of Medical Genetics, Part A, Vol. 140, No. 24, 15.12.2006, p. 2776-2785.

Research output: Contribution to journalArticle

Boyles, AL, Enterline, DS, Hammock, PH, Siegel, DG, Slifer, SH, Mehltretter, L, Gilbert, J, Hu-Lince, D, Stephan, D, Batzdorf, U, Benzel, E, Ellenbogen, R, Green, BA, Kula, R, Menezes, A, Mueller, D, Oro, JJ, Iskandar, BJ, George, TM, Milhorat, TH & Speer, MC 2006, 'Phenotypic definition of chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15', American Journal of Medical Genetics, Part A, vol. 140, no. 24, pp. 2776-2785. https://doi.org/10.1002/ajmg.a.31546
Boyles, Abee L. ; Enterline, David S. ; Hammock, Preston H. ; Siegel, Deborah G. ; Slifer, Susan H. ; Mehltretter, Lorraine ; Gilbert, John ; Hu-Lince, Diane ; Stephan, Dietrich ; Batzdorf, Ulrich ; Benzel, Edward ; Ellenbogen, Richard ; Green, Barth A ; Kula, Roger ; Menezes, Arnold ; Mueller, Diane ; Oro, John J. ; Iskandar, Bermans J. ; George, Timothy M. ; Milhorat, Thomas H. ; Speer, Marcy C. / Phenotypic definition of chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15. In: American Journal of Medical Genetics, Part A. 2006 ; Vol. 140, No. 24. pp. 2776-2785.
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