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8 Cards in this Set
- Front
- Back
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FISH
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– 40 to 250 kb per probe
– detects only the “area under probe” – Shows “position in space” of the change |
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Genomic resolution based on method
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• BAC probes very low FP/FN rate, so only need
one probe to call a deletion/duplication • Oligo probes higher FP/FN rate, so require multiple consecutive probes (usually 5) • Resolution depends on probe spacing |
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Why is CMA Better?
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• More sensitive
– Detect smaller/cryptic abnormalities – About 100-fold increased power over karyotype • More accurate than karyotype – Better define the breakpoints – Less subjective • Can customize array coverage – Could add denser coverage for specific loci of interest • More versatile for sample type – Does not require culture |
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Possible Limitations
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• G-banded karyotyping of large cohorts of individuals with intellectual disability show apparently balanced structural
abnormalities in 1 of 500 patients, and in 1 of 2,000 patients these occur de novo. • Balanced rearrangements make up only about 10% of cytogenetically visible abnormalities in patients with intellectual disability. • an apparently balanced rearrangement revealed submicroscopic imbalance. • Low-level mosaicism may not be detectable by arrays • CMA creates too many Variants of Uncertain Significance (VUS)” |
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Mechanisms for copy number variants to arise
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1. Homologous: Non-allelic homologous recombination (NAHR)
2. Non-homologous end joining (NHEJ) 3. Non-homologous: Fork Stalling and Endplate Switching (i.e. FoSteS) |
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Karyotype Still Recommended in Certain Situations
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• Down syndrome
– Purpose is to look for rearrangement which has high recurrence risk • Turner syndrome – Better able to detect atypical forms of Turner syndrome, including low level mosaicism • FHx of chromosomal rearrangement – Typically balanced in carriers • FHx of multiple (>2) miscarriages – Often caused by balanced rearrangement |
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Clinical prenatal/perinatal situations with clearly documented advantages of CMA
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• Fetal structural abnormalities
• Karyotyping following a fetal/postnatal demise may be unsuccessful in up to 50% of cases because of the lack of viable tissue capable of growing in tissue culture. • Multiple congenital anomalies at birth • Clarification of an abnormal/suspicious karyotype (higher specificity of CMA) – Identification of marker chromosome origin – Look for submicroscopic imbalance if there is a rearrangement |
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What Does an Area of AOH Mean?
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– Segmental uniparental disomy (UPD)
– Close familial relationship between the parents (consanguinity) – Isolated population origin – Region that undergoes limited recombination |
