Journal article
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(24), pp.2776-2785
2006
DOI: 10.1002/ajmg.a.31546
PMID: 17103432
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.
Details
- Title: Subtitle
- 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
- Creators
- Abee L BOYLES - Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United StatesDavid S ENTERLINE - Department of Radiology, Duke University Medical Center, Durham, North Carolina, United StatesEdward BENZEL - Department of Neurosurgery, The Cleveland Clinic, Cleveland, Ohio, United StatesRichard ELLENBOGEN - Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington, United StatesBarth A GREEN - Department of Neurosurgery, University of Miami, Miami, Florida, United StatesRoger KULA - The Chiari Institute, Great Neck, New York, United StatesArnold MENEZES - Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United StatesDiane MUELLER - Division of Neurosurgery, University of Missouri Health Sciences Center, Columbia, Missouri, United StatesJohn J ORO' - Division of Neurosurgery, University of Missouri Health Sciences Center, Columbia, Missouri, United StatesBermans J ISKANDAR - Department of Neurological Surgery, University of Wisconsin-Madison Medical School, Madison, Wisconsin, United StatesTimothy M GEORGE - Department of Surgery, Duke University Medical Center, Durham, North Carolina, United StatesThomas H MILHORAT - Department of Neurosurgery, North Shore University Hospital and Long Island Jewish Medical Center, Great Neck, New York, United StatesPreston H HAMMOCK - Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United StatesMarcy C SPEER - Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United StatesDeborah G SIEGEL - Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United StatesSusan H SLIFER - Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United StatesLorraine MEHLTRETTER - Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United StatesJohn R GILBERT - Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United StatesDiane HU-LINCE - Translational Genomics, Phoenix, Arizona, United StatesDietrich STEPHAN - Translational Genomics, Phoenix, Arizona, United StatesUlrich BATZDORF - Division of Neurosurgery, University of California, Los Angeles, California, United States
- Resource Type
- Journal article
- Publication Details
- American journal of medical genetics. Part A, Vol.140(24), pp.2776-2785
- Publisher
- Wiley-Liss; Hoboken, NJ
- DOI
- 10.1002/ajmg.a.31546
- PMID
- 17103432
- ISSN
- 1552-4825
- eISSN
- 1552-4833
- Language
- English
- Date published
- 2006
- Academic Unit
- Stead Family Department of Pediatrics; Neurosurgery; Otolaryngology
- Record Identifier
- 9984040339402771
Metrics
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