Term
| Is genetic imprinting normal? |
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Definition
| Yes,normal developmental process. Disruption of the normal imprint is a mechanism for a category of genetic diseases. |
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Term
| Normal Mendelian inheritance and the special case of genetic imprinting |
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Definition
1. each parent's genetic contribution is equivalent (except for male chromosomes)
2. Copies from each parent are expected to express equally in the child (biallelic expression)
3. Genomic imprinting is an exception |
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Term
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Definition
Infancy: Hypotonia, feeding difficulties, hypogonadism
Childhood: Uncontrollable appetite (obesity), moderate mental retardation
CAUSED by del(15)(q11q13) in most cases |
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Term
| Angelman Syndrome symptoms |
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Definition
Spasticity and Seizures
Severe mental retardation
Growth retardation
del(15)(q11q13) in most cases |
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Term
| Epigenetic Mechanisms (definition) |
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Definition
DNA modifications that influence gene expression and are heritable BUT reversible
DNA methylation- regulation of gene expression
X inactivation (heritablefrom cell to cell but not from one generation to next)
Genomic imprinting (parent of origin effects transmission though gametes) |
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Term
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Definition
1. Epigenetic process. (heritable but reversible) DNA methylation is a common mechanism for epigenetic control of gene expressions
2. Differential (nonequivalent) gene expression that is dependent on parental origin
3. In a small subset of genes,only the parental/maternal derived copy is expressed (normal for these genes) |
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Term
| Imprinted genes on Chromosome 11 |
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Definition
1. IGF2 (chromosome 11p15)- paternal copy expressed (biallelic expression sometimes)
2. KVLQT1 (potassium channel gene mutated in long QT syndrome) 11p15- maternal copy expressed (biallelic expressed in heart) |
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Term
| Imprinted genes on Chromosome 15 |
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Definition
1. SNRPN (small nuclear ribonucleoprotein polypeptide N) 15q12- paternal expressed
2. UBE3A (ubiquitin protein ligase 3) 15q12- maternal expressed in brain, both copies expressed elsewhere |
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Term
| Biparttite ICR (Imprinting Control region) |
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Definition
| Involved in setting the imprint for the genes during gametogenesis |
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Term
| Total about 60 imprinted genes right now for humans |
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Definition
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Term
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Definition
Epigenetic phenomenon and is associated with DNA methylation
1. imprint switch at gametogenesis
2. pattern maintained throughout development and in the somatic tissues of the adult
3. in gametes, the imprint in reset for the next generation |
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Term
| Another view of imprinting cycle |
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Definition
A. somatic cell with parent0of0origin imprint
B. gametogenesis: imprint is removed and re-imprinted according to sex of parent
C. Parent specific imprints in the zygote |
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Term
| Role of imprinting in genetic disease |
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Definition
Parent-of-origin effect on disease
When only one allele is normally active, disease presents when that allele is disabled by any one of multiple mechanisms |
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Term
| Deletion "hotspot" includes both PWS and AS critical regions |
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Definition
Most affected people have critical region deletion (kinda big 4-6Mb) with relatively uniform breakpoints
46,XX,del(15)(q11q13)
Parent of origin effect:
paternal deletion======PWS
maternal deletion======AS |
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Term
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Definition
BP1/2/3
Unequal crossover between low copy repeats at BP1/BP2 and BP3 causing microdeletion
Class I (40% deletions)- BP1/BP3
Class II (50% deletions)- BP2/BP3 |
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Term
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Definition
NO paternal contribution of 15q12 critial region (1 or 2 maternally derived copies)
1. 70% paternal deletion(mocrodeletion)
2. 28% maternal UPD
3. 2% mutation of imprinting center |
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Term
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Definition
NO maternal contribution of 15q12 critial region (1 or 2 paternally derived copies)
1. 70% maternal deletion(microdeletion)
2. >5% paternal UPD
3. <5% mutation of imprinting center
4.10% UBE3A point mutations (fmilial)
5.10% unknown |
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Term
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Definition
Situation where an individual inherits both chromosomes of one homologous pair from a single parent and no copy of that chromosome from the other parent
Individual has correct amount of genetic material, but parental origin is abberant
RARE |
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Term
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Definition
UPD is caused by two separate nondisjunction events in the gametogenesis and/or embryogenesis of a single individual
Trisomy rescue: trisomy caused by (maternal) meiotic nondisjunction followed by chromosome loss through mitotic nondisjunction |
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Term
| UPD needs how many independent errors? |
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Definition
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Term
| Low copy repeats provide a common mechanism for genomic imbalance (fact) |
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Definition
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Term
| Cross over in misaligned segments leads to 2 abnormal products |
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Definition
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Term
| Low Copy repeats and Segmental Aneuploidy |
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Definition
LCRs are abundant and dispersed throughout the genome
Recombination between misaligned repeats in a common mechanism leading to changes in copy number. :
1. Normal copy number variation- CNV
2. Segmental aneuploidy syndromes- microdeletion syndromes are associated with partial monosomy with deletion of the critical region |
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Term
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Definition
Standard karyotype
FISH
Array Comparative Genomic Hybridization
(is there a suspected genetic diagnosis? implications of potential test results? possible follow up testing?) |
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Term
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Definition
del 17 (q11q11)
diagnosed with FISH- partial monosomy of 7q |
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Term
| Array CGH (what is it and the ratios) |
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Definition
Comparative Genomic Hybridization via microarray
Combine patient DNA and control DNA- appply to microarray and evaluate relative copy number across genome
Normal/balanced= 1:1 (patient:control)
Microdelection (partial monosomy)= 1:2
Microduplication (partial trisomy)= 3:2 |
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Term
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Definition
1. Patient and control DNA are labeled with fluorescent dyes and applied to the microarray
2. Both DNAs compete to attach, or hybridize to the microarray
3. The microarray scanner measures fluorescent signal intensity |
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Term
| What info does an Array CGH give? |
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Definition
Provides precise info about the AMOUNT of genomic material relative to a reference genome but NOT the nature of the rearrangement
FISH can give info about the types of rearrangement and possible recurrence risks
Karyotypes may be needed for other family members |
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Term
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Definition
1. Detects chromosome imbalance identified by traditional karyotyping in addition to imbalances that karyotyping can't detect
2. Simultaneously and rapidly evaluates thousands of regions of the genome
3. Identifies and further characterizes chromosome imbalances identified by karyotyping (UNBALANCED rearrangements)
4. Does not need living cells
5. faster results |
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Term
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Definition
CANNOT DETECT: balanced rearrangements, some polyploidies, basepair changes in DNA sequence gains or losses in regions of the genome not covered by the array
NORMAL array does not rule out most genetic conditions. ABNORMAL array can have unclear clinical applications |
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Term
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Definition
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Term
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Definition
1. Balanced arrangements (with no gain/loss)- balanced translocations, reciprocol insertions, inversions)
2. Some polyploidies
3. Changes in gene DNA sequesnces (point mutations, intragenic insertions/deletions, triplet repeat expansions)
4. Gains/losses not covered by array.
(normal results don't rule out msot genetic diseases, bc many syndromes caused by genetic changes other than deletions/duplications or chromosomal material) |
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Term
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Definition
PROS: genomes-wide, very sensitive detection of genomic imbalance
CONS: Can't detect balanced rearrangements, results often complex/ambiguous, expensive, methodology not standardized |
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Term
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Definition
1. Assists in clarifying whether DNA dosage alteration in the patient is causative of the patient's clinical findings (New/de novo finding suggests that the DNA dosage alteration may be causative)
2. Assists in providing recurrence risks to the family ( a parent may carry a balanced chromosome that is unbalanced in the patient)
3. Assists in identifying other family members at risk |
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Term
| Clinical guidelines for aCGH |
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Definition
recommended at first-tier diagnostic test for people with developmental disabilities or congenital anomalies- higher yield than karyotype/better detections of duplications that FISH/more precise characterization of abnormalilty
Interpretation is complicated by normal (nonpathogenic) variations in copy number |
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Term
| Breakage and rearrangements of chromosome segments (and importance) |
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Definition
Visible rearrangements seen in the microscope as a deviation from the normal banding pattern
Structural abnormalities involving very small segments may not be microscopically visible. Submicroscopic abnormalities need molecular approaches for detection
IMP:
Phenotype abnormalities/reproductive risks/importance of acquired abnormalities in cancer |
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Term
| Balanced vs. Unbalanced Structural Abnormalities |
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Definition
Balanced: Novel rearrangement with the same net amount of genomic material/normal phenotype/reproductive risk
Unbalanced: Rearrangement with extra and/or missing genetic material, high likelihood of phenotypic abmornality |
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Term
| Unbalanced Structural Abnormalities (types) |
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Definition
1.Partial trisomy- 3 copies of the specific chomosome segment
2. Partial monosomy- 3 copies of a specific chromosome segment
(high risk of abnormal phenotype)
3. de novo- new structual abnormality (present in offspring but no in either parent)
4. Familial- abnormalities that segregate through pedigree balanced, but sometimes give rise to an unbalanced offspring
5. Constitutional- in all cells of body
6. Acquired- abnormality arrising in somatic cell or a single tissue (cancer lineages) |
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Term
| ALTERNATE segregation (Meiotic segregation of reciprocal translations) |
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Definition
Most likely segregation pattern for the majority of translocations
Gamete gets the two normal or two abnormal chromosomes
Balanced
Phenotypically normal offspring |
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Term
| ADJACENT Meiotic Segregation of reciprocol Transpositions |
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Definition
Risk-associated segregation patterns
Gamete gets one normal and one abnormal chromosome
Unbalanced (partial trisomy/monosomy)
High risk of phenotypic abnormalities or SAb |
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Term
Reciprocol transpositions
(incidence and gametes made) |
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Definition
Balanced translocation carriers: 1 in 500-1000
Often Familial
Three types of gametes made:
1.normal with ok phenotype
2.balanced with normal phenotype
3. abnormal or unbalanced with abnormal phenotype or miscarriage |
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Term
| Clinical consequences of Reciprocol transpositions |
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Definition
Hard to predict bc each transposition is unique.
For many translocations, unbalanced segregants are nonviable
The risk of liveborn offspring with multiple abnormalities may be significant since slamm segmental aneuploidies are better tolerated than complete aneuploidies |
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Term
| Clinical Considerations of Reciprocal Translocations |
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Definition
1. Since pregnancy loss is common in the general population (about 15% of clinically recognized pregnancies), evaluation is indicated only after RECURRENT losses
2. 3-5% of couples with recurrent losses have a chromosome abnormality (reciprocal trans, Robertsonian, female X chromosome mosaicism)
3. Imp of family history
4. Role of prenatal diagnosis and other reproductive strategies |
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Term
Robertsonian translocations
(reproductive outcomes for 14q21q translocations) |
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Definition
1. Translation down syndrome
10-15% (maternally derived)
1% (paternally derived)
2. Remaining adjacent segregants are lethal
3. Equal proportions normal karyotype and balanced carrier (about 50% each from mother and 50% from father) |
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Term
| Definition of Robertsonian Translocations |
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Definition
1. Involves two acrocentric chromosomes- RT involving chromosomes 13 or 21 carry the risk of live births with the associated trisomy
2.Increased miscarriage risk associated with any Robertsonian |
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Term
| Homologous Robertsonians/ ISOCHROMOSOMES |
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Definition
1.Fusion chromosome- two copies of the same acrocentric long arm ( like rob14q14q or rob 21q21q)
2.Possibly caused by centromere misdivision or long arm fusion event
3. Balanced carriers have a chromosome number of 45
4. balanced carriers have close to a 0% chance to have a healthy offspring |
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Term
| Examples of Isochromosomes |
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Definition
i(Xq) = Turner syndrome [46,X,i(Xq)]
i(21q) = translocation DOWN SYNDROME [46,XY,i(21q)] |
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Term
| Deletions and Duplications (partial monosomy and partial trisomy) |
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Definition
1. Phenotypic consequences are driven by the net imbalance of genomic material (deletion vs. duplication and its size)
2. May arise de novo in the pt
3. May be an unbalanced segregant of a familial rearrangement (reciprocal translocation or inversion)
4. Diagnosis by conventional karyotype, FISH or aCGH |
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Term
| Indications for Chromosome Analysis |
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Definition
1. Confirm recognizable syndrome
2. Multiple congenital anomalies in fetus, stillborn or infant
3. Family members of known case
4. Couples with multiple fetal losses/infertility
5. Ambiguous genitalia/delayed puberty
6. Mental retardation with dysmorphia or anomalies
7. Prenatal diagnosis for maternal age or other indications |
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Term
| Methods for Chromosome Analysis |
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Definition
1.Traditional Cytogenic Analysis- viable cells like lyphocytes usually needed, short term CULTURE to obtain mitotically active cells, arrest in metaphase, harvest and prep for microscopy
2.Molecular approaches may use metaphase cells, interphase cells or genomic DNA |
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Term
| Syndromes caused by genomic inbalances |
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Definition
| A disease caused by deletion of multiple, adjacent genes in the CRITICAL REGION. Caused by recombination between misaligned repeats and other related mechanisms |
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Term
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Definition
Chromosome deletions (partial monosomies) too small for reliable detection by routine methods
LImited resolution of routine chromosome analysis (banded chromosomes)- interstitial and terminal deletions <5 Mb can't be detected reliably
Imp. class of genetic syndomes ( Almost all pts. have developmental disability plus syndrome-specific anomalies) |
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Term
Unequal crossover of low-copy repeats at breakpoints (PWS)
Should be prefect allignment of homologous DNA on non-sister chromatids |
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Definition
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Term
| Abnormalities of chromosome structure are a imp category of genetic diseases and are a leading cause of intellectual disability and pregnancy loss |
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Definition
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Term
| Metacentric/Submetacentic/Acrocentric |
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Definition
Meta- 2
Submeta-18
Acro- 13,14,15,21,22
(classified by size and centromere position) |
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Term
| What is needed for chromosome stabilty? |
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Definition
| 1 centromere and 2 terminal telomeres |
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Term
| Phenotypic Consequences of Unbalanced Karyotypes |
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Definition
In general autosomal imbalance causes:
1. developmental delay (interllectual diasability)
2. growth delay
3. facial dysmorphology and physical mafformations
4. congental organ malformations, like heart defects |
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Term
| Additional consequences of unbalanced karyotypes |
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Definition
Presence of mosaicism (abnormal and normal cell lines)- generally LESS severe phenotype
Imbalance involving sex chromosomes- generally LESS severe phenotype than autosomal imbalance
Larger the imbalance, greater the risk of lethality (monosomy WORSE than trisomy) |
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Term
| Reciprocal Translocations |
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Definition
1.Two break, reciprocal rearrangement
2. Exchange of segments between two nonhomologous chromosomes
3. Random- breakpoints can be anywhere, in any two chromosomes
4. Balanced carrier- phenotypically normal with reproductive risks |
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Term
| Radon about Robertsonian Translocations |
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Definition
Long arm fusion of any two acrocentric chromosomes0 fusion chromosome has a single functional chromosome
Balanced carrier has a chromosome number of 45
Acrocentric short arm material is usually lost. It is redundant and its loss cause no phenotypic consequence |
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