Structural And Chromosomal Abnormalities Flashcards
What are the structural chromosomal abnormalities ?
Balanced(no gain or loss of genetic material )
Unbalanced (gain or loss of genetic material)
What is a reciprocal translocation?
Exchange of genetic material between non-homologous chromosomes
W(at are the effects of reciprocal translocation?
When the reciprocal translocation occurs in somatic cells, the effects may be
- May have no eff3cts(silent)
- transformation to cancer abs increased growth rate of cells
If the ciprocal translocation is present in the germ line cells, then there is a higher incidence of spontaneous abortions in the carrier
Contrast alternate and adjacent segregation of reciprocal translocation
Alternate segregation- normal gamete and translocation carrier
Adjacent-fertilization with these gametes mostly incompatible with life- occasionally resulting in deletion or duplication syndrome
How can reciprocal translocation cause a fusion gene?
t(9;22)—> chronic myelogenous leukemia (CML)
Activation of an oncogene —> cancer Philadelphia chromosome t(9;22)—> activation of BCR-ABL tyrosine kinase which is a proto-oncogene in hematopoietic cells
Reciprocal translocation changing gene expression
t(8;14)—> burkitt lymphoma
Dysregulation of c-Myc gebe expression, leading to cancer
How does BCR-ABL phenotype manifest?
The abnormal BCR-ABL abnormal protein, tyrosine kinase is produced, that stimulates uncontrolled division in the cells
What is Robertsonian translocation?
Occurs between acrocentric chromosomes
-chromosomes 13,14,15,21,22
There is loss of the short arms of the two chromosomes
-the satellite structures in the acrocentric chromosomes contain multiple copies of genetic material for RNA
Fusion of the long arms I’d the two chromosomes
What are the effects of Robertsonian translocation?
Alternate segregation can result in:
-normal gamete (gamete 1)
-gamete with the derivative chromosome (gamete 2), that results in a Robertsonian translocation carrier on fertilization
Adjacent segregation results in trisomy of the respective chromosome on fertilization.
-Gamete 3 would result in trisomy 14, that is not compatible with survival, and results in spontaneous abortions
-Gamete 4 would result in trisomy 21 (Down syndrome) on fertilization
Down syndrome due to Robertsonian translocation occurs for about 2-5% of children with Down syndrome
How can Robertsonian translocation result in a spontaneous abortion?
Derivative chromosome 14 has the long arm of chromosome 21
Robertsonian translocation between chromosomes (no. 21/14) in relation to the history of spontaneous abortion in a family
What are the indications for cytogenic or cytogenetic testing f9r a Microdeletion syndrome?
- Unexplained developmental delay or autism spectrum disorder
- Congenital anomalies/Dysmorphic features
- Suspected deletion or duplication syndrome
Describe large deletion syndromes
- approximately 5 Mb or larger are usually detected by standard karyotype
- Must effect binding pattern though
- some very large deletions (about 10 Mb) appear normal by karyotype
- Some very large duplications May appear normal by karyotype
Descr8be small deletions
Smaller than 4 Mb may not be detected by standard karyotype, called “Microdeletion”
Summarize Microdeletion syndromes
Well characterized common deletion syndromes have historically been tested by FISH
Microarray CGH can now be used to detect common deletion syndromes, and can detect uncharacteristic very small deletions and duplications
Summarize microarray CGH
Each spot on the array is an immobilized probe for a specific place in the genome
-Allows the use of almost a million probes (high density))
What are the steps in microarray CGH?
- Label DNA with different fluorescent dyes
- Mix equimolar amounts of labelled DNA
Apply DNA mix to glass slide with high density array of different DNA probes with known location in the human genome
What causes Cri-du-chat syndrome?
Deletion of chromosome 5p
-cru-di-chat syndrome
46, XX,del(5)(p15.3)(pter) or 46,XY,del(5)(p15.3)(pter)
What are the featuresof Cri-du-chat syndrome?
- High pitched, cat-like cry
- Micrognathia which influences the cat-like cry and later, speech problems
- Severe intellectual disability
- Microcephaly
- Hypertelorism (widely spaced eyes)
What are the Cri-du chat syndrome diagnostic tests ?
Sometimes the deletion that leads to Cri-du chat syndrome will be detected by karyotype, but not al2ays
FISH for diagnosis of Cri du chat syndrome
CGH for diagnosis of Cri du chat syndrome: array CGH rrvelead a 3.6 Mb deletion at 5p15.33-13.3
What is 22q11.2 deletion syndrome ?
Aka velocardiofacial syndrome or DiGeorge
Most contiguous gene (Microdeletion) disorder in humans, about 1:4000 to 1:6000
What are the features of microdeletion of chromosome 22q11.2?
- congenital heart defects
- absence of thymus (thymic aphasia)- might cause immunological problems
- cleft lip & palate ; maybe speech difficulty
- learning disability
- facial abnormalities include long midface, narrow palpebral fissures, prominent nasal root and bulbus nasal tip, ear dysmorphology
- Increased risk for schizophrenia
What is Wolf-Hirschhorn syndrome?
A few genes on chromosome 15 are monogenic (only one allele is expressed)
- Two genes in PARTICULAR are SNRPN & UBE3A
- One copy of each of these genes are methylated, thus silenced
- Prader Willi syndrome & Angelman syndrome are due to deletions of chromosome 15q11 to 15q13
- Prader Willi syndrome is due to deletion of paternally chromosome 15q11-13 which includes SNRPN gene
- Maternal gebe SNRPN is methylated, thus turned off
- Prader Willi syndrome is due to deletion of paternally chromosome 15q11-13 which includes SNRPN gene
Angelman syndrome is due to deletion of maternally chromosome 15q11-13 which includes the UBE3A gene
What. Happens in chromosome 15q11-13 under normal conditions ?
SNRPN GENE
-One copy, the paternal copy of the SNRPN gene is expressed in a person (maternal copy is methylated and turned off
UBE3A GENE
-one copy, the maternal copy of the UBE3A gene is expressed in a person (paternal copy is methylated and turned off)
What syndrome results from paternal deletion of SNRPN ?
Prader Willi syndrome
What syndrome results from deletion in a UBE3A gene?
Angelman syndrome
Contrast Prader- Willis syndrome and Angelman syndrome symptoms
Prader Willis. Syndrome
- eating disorder-hyperphagia
- developmental delay
- hypotonia at birth
- hypogonadism
- distinctive facial features
Angelman syndrome
- unprovoked smiling and laughing
- jerky uncoordinated movement
- lack of speech
- hypotonia
- severe developmental delay
What May cause uniparental disomy?
Might occur by trisomy rescue mechanism
-non-disjunction of chromosomes while developing gamete, then upon fertilization there is a trisomy. The zygote May try to correct by kicking out one the excess chromosomes
Uniparental disomy might occur if a fertilized embryo is monosomic. The single chromosone that remains might be duplicated to recreate the diploid state
What are the two theories of uniparental disomy?
- Trisomy rescue
2. Chromosome reduplication
What are inversions?
May be pericentric (involves at the centromere) or paracentric doesn’t involve centromere)
Usually balanced & no clinical problems in carriers
Inversions usually result in a change in the banding pattern of the chromosome and can be identified by karyotype analysis
What is the effect of inversions during crossover in meiosis ?
Crossover during meiosis results in duplication or deletion of segments of the chromosome (unbalanced genetic material). The gametes with a centric and dicentric chromosomes aren’t viable. Carriers of inversions May be asymptomatic, but they have a high risk of spontaneous abortions
What are isochromosomes?
There is loss of one arm of a chromosome & duplication of the other arm
X chromosome: long arms of the X chromosome join to form a isochromosome
Girls with isochromosome X have Turner syndrome
Typically results in chromosomal and gene dosage imbalance
Isochromosome of an autosome is lethal
-May be tolerated if mosaic
What is the X-isochromosome i(X)?
Some children with Turner syndrome have an isochromosome of one of the X chromosomes
- They have only one of the short arm of X chromosome
- The isochromosome is typically inactivated
Haploinsufficiency of genes on the p arm that escape X inactivation thought to give rise to phenotype
What are ring chromosomes?
A ring chromosome forms when a chromosome loses genetic material at the terminal portions& the ends fuse to form a ring like structure
In the radiation worker fir whom this cell culture was evaluated for structural chromosome aberrations, a total of 4 cells each containing one ring were identified in a sample of only 100 cells
