How to cite this article: Boyles AL, Enterline DS, Hammock PH, Siegel DG, Slifer SH, Mehltretter L, Gilbert JR, 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. Am J Med Genet Part A 140A:2776–2785.
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†
Article first published online: 13 NOV 2006
Copyright © 2006 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 140A, Issue 24, pages 2776–2785, 15 December 2006
How to Cite
Boyles, A. L., Enterline, D. S., Hammock, P. H., Siegel, D. G., Slifer, S. H., Mehltretter, L., Gilbert, J. R., Hu-Lince, D., Stephan, D., Batzdorf, U., Benzel, E., Ellenbogen, R., Green, B. A., Kula, R., Menezes, A., Mueller, D., Oro', J. J., Iskandar, B. J., George, T. M., Milhorat, T. H. and Speer, M. C. (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. Am. J. Med. Genet., 140A: 2776–2785. doi: 10.1002/ajmg.a.31546
- Issue published online: 21 NOV 2006
- Article first published online: 13 NOV 2006
- Manuscript Accepted: 29 SEP 2006
- Manuscript Received: 17 MAY 2006
- American Syringomyelia Alliance Project
- NIH. Grant Numbers: NS26630, ES11375, ES11961
- Chiari type I malformation;
- genome wide linkage screen;
- cranial morphology
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. © 2006 Wiley-Liss, Inc.