Institution
Hereditary Disease Foundation
Other•New York, New York, United States•
About: Hereditary Disease Foundation is a other organization based out in New York, New York, United States. It is known for research contribution in the topics: Huntington's disease & Genetic linkage. The organization has 11 authors who have published 40 publications receiving 12142 citations. The organization is also known as: HDF.
Papers
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TL;DR: In this article, the authors used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect, which is expanded and unstable on HD chromosomes.
7,224 citations
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TL;DR: The chromosomal localization of the Huntington's disease gene is the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder.
Abstract: Family studies show that the Huntington's disease gene is linked to a polymorphic DNA marker that maps to human chromosome 4. The chromosomal localization of the Huntington's disease gene is the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder.
2,211 citations
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TL;DR: It is concluded that mRNA changes are not attributable to cell loss alone, and data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.
Abstract: Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.
736 citations
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TL;DR: HD appears to be the first human disease of genetically documented homozygosity that displays complete phenotypic dominance, indicating that the normal allele may play a role in ameliorating the disease process.
Abstract: Careful comparison of symptomatic individuals with normal controls has revealed the primary biochemical abnormality in many human genetic diseases, particularly recessive disorders1. This strategy has proved less successful for most human disorders which are not recessive, and where a single copy of the aberrant gene has clinically significant effects even though the normal gene product is present. An alternative approach that eliminates the impediment of a normal protein in affected individuals is to study homozygotes for the mutant allele2. For virtually all dominant human disorders in which homozygotes have been described, symptoms have been significantly more severe in the homozygote than in the heterozygote3. Thus, these disorders do not conform to the classical definition of dominance which states that homozygotes and heterozygotes for a defect are phenotypically indistinguishable3–5. Instead, they display incomplete dominance, indicating that the normal allele may play a role in ameliorating the disease process. The D4S10 locus, defined by the probe G8 and linked to the gene for Huntington's disease (HD), has permitted us to identify individuals with a high probability of being homozygous for this autosomal dominant neurodegenerative disorder6–9. These homozygotes do not differ in clinical expression or course from typical HD heterozygotes. HD appears to be the first human disease of genetically documented homozygosity that displays complete phenotypic dominance.
361 citations
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TL;DR: A software tool called ExpansionHunter is developed that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length, and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
Abstract: Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
254 citations
Authors
Showing all 11 results
Name | H-index | Papers | Citations |
---|---|---|---|
P. Michael Conneally | 51 | 82 | 11911 |
Nancy S. Wexler | 37 | 63 | 22597 |
Ethan R. Signer | 31 | 65 | 4604 |
Penchaszadeh Gk | 21 | 27 | 3692 |
Carl D. Johnson | 7 | 10 | 964 |
Ethan Signer | 6 | 7 | 682 |
Michael Basson | 6 | 6 | 5891 |
Alice Wexler | 5 | 9 | 907 |
S A Roberts | 4 | 4 | 156 |
Nancy S. Wexler | 1 | 1 | 52 |
Allan J. Tobin | 1 | 1 | 4 |