Term
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Definition
| the tendency for genes or segments of DNA closely positioned along a chromosome to segregate together at meiosis and thus, be inherited together |
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Term
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Definition
Also called INDIRECT DNA alanysis
The use of many DNA markers (normal variants) that are near ot within the gene of interest to track within a family the inheritance of a disease causing mutation in that gene |
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Term
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Definition
| An identifiable segment of DNA with enough variation between individuals that its inheritance and co-inheritance with alleles of a given gene can be traced. |
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Term
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Definition
| For two or more closely linked markers,the alleles contained on the same chromosome ;haplotype |
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Term
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Definition
| In a population, co-occurence of specific alleles at a higher frequency than would be predicted by random chance- over representation of specific haplotypes |
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Term
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Definition
| Molecular genetic testing to identify a set of closely linked segments of DNA- used in linkage analysis or when a given trait is in linkage disequilibrium with a marker or set of markers |
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Term
| recombination frequency determines extent of linkage (fact) |
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Definition
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Term
| Genetic testing (direct vs. indirect (linkage)) |
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Definition
Direct= probe on the allege/gene
Indirect= testing of unknown disease allele using multiple, closely linked, flanking markers [any known variant that is in linkage with an (unknown) causative mutation potentially can be used for linkage analysis] |
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Term
| Utility of Linkage Analysis/ Importance of Haplotype (phase) |
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Definition
When direct DNA analysis is not possible.
When the disease causing mutation within the gene of interest is unknown in a specific family
Must be established in each family.
Only in the rare instance of linkage disequilibrium is a specific haplotype highly likely to be associated with a specific disease-causing mutation. |
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Term
| Limitations of Linkage Analysis |
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Definition
The accuracy of the linkage depends on:
1. Accuracy of clinical diagnosis
2. Distance between the disease-causing mutation and the markers. Linkage analysis may yield false positives/false negative results if recombination between markers occurs during gamete formation. Risk of recombination is lowest if intragenic markers are used.
3. Informativeness of genetic markers in in the family. In MOST situations, a marker that is homozygous is not informative. A marker that is heterozygous MAY be informative. |
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Term
| TriNucleotide Repeat Expansion Disorders TNR |
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Definition
Clinically diverse disorders that share a novel mutational mechanism
Genes containing tandem repeats of 3 basepairs.
Unstable expansion of repeat copy number from one generation to the next.
Expansion disrupts normal gene function, causing neurological disease |
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Term
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Definition
1. X-linked
2. Most common form of inherited mental retardation (1 in 5000 males)
3. CGG expansion in 5' untranslated region of FMR1 gene- expansion accompanied by DNA methylation, which shuts down gene expression
4. Full mutation: males (100% affected) females (50% affected) |
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Term
| CGG repeat expansion in Fragile X (number of repeats vs outcome) |
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Definition
1. 6-54 repeats= normal allele= STABLE
2. 55-200 repeats= premutated allele= stable/unstable
3. 200-1300 repeats= UNSTABLE= Fragile X syndrome
5' untranslated region of FMR gene |
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Term
| Normal range of repeat copy number (for fragile X) |
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Definition
| MOST people have 25-32 repeats on the FMR1 alleles |
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Term
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Definition
Affected males is 1 in about 5000 males
Unaffected premutation carrier females is 1 in about 100 females (variable size and variable risk for expansion)
Minor phenotypic abnormalities, including premature ovarian failure and FXTAS (fraX associated tremor/ataxia syndrome) may be present in premutation carriers |
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Term
| Two main categories of Trinucleotide Repeat Disorders |
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Definition
1. Trinucleotide repeats expansions in NONCODING regions that interfere with normal gene expression- loss of function like in Fragile X
2. Expansions of Polyglutamine (CAG)n tracts in CODING sequence= neuronal degeneration [gain of function like in Huntingtons Disease) |
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Term
| TNR expansions: Pathogenic Mechanisms |
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Definition
1. Fragile X- expansion on 5' UTR interferes with FMR1 expression
2. Myotonic Dystrophy- expansion in 3' UTR in DMPK gene disrupts normal gene slicing of other genes
3. Huntington Disease- expansion of polyglutamine tract causes protein to form toxic aggregates |
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Term
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Definition
1. Autosomal Dominant
2. Adult onset neurodegenerative disorder
3. Gene product (huntingtin) includes polyglutamine tract encoded by (CAG)n
Normal alleles= 10-35 CAg repeats (alleles in normal range are variable but stable)
Disease alleles= >35 CAG repeats (meiotically unstable, continued expansion) |
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Term
| Genotype/Phenotype correlation in HD |
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Definition
| Larger repeat number associated with earlier onset age |
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Term
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Definition
General feature of TNR disorders
Progressively earlier onset/increased severity in successive generations
Caused by successive increase in repeat copy number from generation to generation
[continued expansion of repeat copy number in descendants associated with increased severity] |
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Term
| Molecular Mechanism of TNR expansion |
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Definition
1. Likely mechanism- strand slippage or altered DNA conformation during DNA replication
2. Some disorders (Huntington) most unstable in male meiosis
3. Some disorders (Fragile X) most unstable in female meiosis
4.Minor instability during mitosis- somatic mosaicism |
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