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
- 13 November 2006
- journal article
- research article
- Published by Wiley in American Journal of Medical Genetics Part A
- Vol. 140A (24), 2776-2785
- https://doi.org/10.1002/ajmg.a.31546
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.Keywords
This publication has 56 references indexed in Scilit:
- Chiari I malformation and neurofibromatosis type 1Pediatric Neurology, 2004
- Prospective Analysis of Presenting Symptoms Among 265 Patients With Radiographie Evidence of Chiari Malformation Type I With or Without SyringomyeliaJournal of the American Academy of Nurse Practitioners, 2004
- Shprintzen-Goldberg syndrome: A clinical analysisAmerican Journal of Medical Genetics, 1998
- Accurate Inference of Relationships in Sib-Pair Linkage StudiesAmerican Journal of Human Genetics, 1997
- Pallister‐Killian syndrome detected by fluorescence in situ hybridizationAmerican Journal of Medical Genetics, 1995
- The Association of Chiari Type I Malformation and Neurofibromatosis Type 1Clinical Pediatrics, 1993
- Birth prevalence studies of the Crouzon syndrome: comparison of direct and indirect methodsClinical Genetics, 1992
- NeurofibromatosisSurgical Neurology, 1986
- Syringomyelia as a sequel to traumatic paraplegiaSpinal Cord, 1981
- Size of posterior fossa in Chiari type 1 malformation in adultsActa Neurochirurgica, 1978