A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10.

Crouzon craniofacial dysostosis (CFD) is an autosomal dominant craniofacial disorder characterized by premature craniosynostosis, shallow orbits and hypoplastic maxilla. To map the gene responsible, we have used a mapping strategy of testing for linkage to known developmental genes. Analysis of a large kindred established linkage between CFD and three loci (D10S190, D10S209 and D10S216) that span a 13 cM region on chromosome 10q. A maximum pairwise lod score of 4.42 (theta = 0) at D10S190 was obtained and the addition of a second kindred produced a combined pairwise lod score of 5.32 (theta = 0) at the same locus. The developmental gene, PAX2, located within this region, is an attractive candidate gene.

Amplification of epidermal growth factor receptor gene in gliomas: histopathology and prognosis.

In order to evaluate the incidence and prognostic significance of gene amplification in primary brain neoplasms we measured the number of gene copies per cell of three oncogenes (epidermal growth factor receptor [EGFR] gene, N-myc, C-myc) and syntenic control genes in 40 specimens using quantitative DNA dot blots. We observed EGFR gene amplification in astrocytomas and anaplastic astrocytomas with approximately the same incidence as in glioblastoma multiforme (33%), although large amplifications were only seen in glioblastoma multiforme. Fourteen patients had a supratentorial glioblastoma multiforme; six had EGFR gene amplification and eight had either normal EGFR gene copy number or elevated EGFR copy number attributable to extra copies of chromosome 7. Patients with gene amplification had shorter survival than patients without gene amplification (p = 0.01). The observed difference in survival was not likely to be due to group differences in age, sex, treatment, or histopathology.

Initial results of a genome survey for novel Alzheimer's disease risk genes: association with a locus on the X chromosome.

As the initial step in a systematic genome survey, 16 simple sequence tandem repeat polymorphisms that span the X chromosome at an average spacing of 10 cM were examined for allelic associations with typical-onset Alzheimer's disease (AD). The efficiency of this survey was substantially enhanced by genotyping pools of genomic DNA from 50 autopsy-confirmed AD cases and 50 autopsied controls who were similar in sex ratio, race, and age at death. The frequency of the DXS1047 202-bp allele was twice as common among AD cases (0.45+/-S.E. 0.06) than controls (0.22+/-S.E. 0.05), a finding that was reproduced in an independent and geographically disparate sample. Consistent with Hardy-Weinberg equilibrium, the proportion of women with AD who carried the 202-bp allele, 73% was nearly double that observed for men with AD, 38%. However, the frequency of the 202-bp allele was similar for men and women and the presence of this allele did not affect the age at onset of dementia in either sex. Furthermore, the frequency of the DXS1047 202-bp allele in AD cases and controls was unaffected by the APOE genotype, indicating that these two loci modulate AD risk independently. Finally, the frequency of the 202-bp allele among 50 autopsy-confirmed cases of Parkinson's disease (0.29+/-S.E. 0.06) was indistinguishable from the control value, reflecting relative specificity for this allelic association with AD.

Initial results of a genome survey for novel Alzheimer's disease risk genes: association with a locus on the X chromosome.

As the initial step in a systematic genome survey, 16 simple sequence tandem repeat polymorphisms that span the X chromosome at an average spacing of 10 cM were examined for allelic associations with typical-onset Alzheimer's disease (AD). The efficiency of this survey was substantially enhanced by genotyping pools of genomic DNA from 50 autopsy-confirmed AD cases and 50 autopsied controls who were similar in sex ratio, race, and age at death. The frequency of the DXS1047 202-bp allele was twice as common among AD cases (0.45 +/- S.E. 0.06) than controls (0.22 +/- S.E. 0.05), a finding that was reproduced in an independent and geographically disparate sample. Consistent with Hardy-Weinberg equilibrium, the proportion of women with AD who carried the 202-bp allele, 73% was nearly double that observed for men with AD, 38%. However, the frequency of the 202-bp allele was similar for men and women and the presence of this allele did not affect the age at onset of dementia in either sex. Furthermore, the frequency of the DXS1047 202-bp allele in AD cases and controls was unaffected by the APOE genotype, indicating that these two loci modulate AD risk independently. Finally, the frequency of the 202-bp allele among 50 autopsy-confirmed cases of Parkinson's disease (0.29 +/- S.E. 0.06) was indistinguishable from the control value, reflecting relative specificity for this allelic association with AD.

Asymmetrical ocular pursuit with posterior fossa tumors.

We report two patients with posterior fossa neoplasms who demonstrated asymmetrically impaired horizontal ocular pursuit documented with electrooculography. One patient had impaired pursuit contralateral to a pontomedullary lesion, whereas the second patient had impaired pursuit ipsilateral to a pontocerebellar lesion. These patients demonstrate that posterior fossa lesions may impair ocular pursuit either contralaterally or ipsilaterally unlike cerebral hemispheric lesions, which impair ocular pursuit ipsilaterally or bilaterally.

A genome survey for novel Alzheimer disease risk loci: results at 10-cM resolution.

We completed a systematic survey of the human genome, conducted at an average resolution of 10 cM, for the identification of simple sequence tandem repeat polymorphisms (SSTRPs) that target new risk genes for Alzheimer disease (AD) by virtue of linkage disequilibrium. The efficiency of our association study was enhanced by genotyping pools of DNA from autopsy-confirmed cases with AD and matched controls. Allelic associations with AD were observed for 6 of the 391 SSTRPs in the CHLC Human Screening Set/Weber Version 6 (Research Genetics, Inc., Huntsville, AL): D1S518, D1S547, D10S1423, D12S1045, D19S178, and DXS1047. These allelic associations were replicated in an independent sample of autopsied AD cases and controls recruited from a geographically disparate site. The association of the large D19S178 alleles with AD appeared to arise from linkage disequilibrium with the APOE epsilon 4 allele, whose effect on increasing the risk of AD has been established. None of the remaining SSTRPs was in close proximity to loci previously reported to influence the risk of developing AD. Instead, they may identify five novel AD susceptibility loci.