Structural And Chromosomal Abnormalities

Question 1

What are the structural chromosomal abnormalities ?

Answer 1

Balanced(no gain or loss of genetic material )

Unbalanced (gain or loss of genetic material)

Question 2

What is a reciprocal translocation?

Answer 2

Exchange of genetic material between non-homologous chromosomes

Question 3

W(at are the effects of reciprocal translocation?

Answer 3

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

Question 4

Contrast alternate and adjacent segregation of reciprocal translocation

Answer 4

Alternate segregation- normal gamete and translocation carrier

Adjacent-fertilization with these gametes mostly incompatible with life- occasionally resulting in deletion or duplication syndrome

Question 5

How can reciprocal translocation cause a fusion gene?

Answer 5

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

Question 6

How does BCR-ABL phenotype manifest?

Answer 6

The abnormal BCR-ABL abnormal protein, tyrosine kinase is produced, that stimulates uncontrolled division in the cells

Question 7

What is Robertsonian translocation?

Answer 7

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

Question 8

What are the effects of Robertsonian translocation?

Answer 8

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

Question 9

How can Robertsonian translocation result in a spontaneous abortion?

Answer 9

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

Question 10

What are the indications for cytogenic or cytogenetic testing f9r a Microdeletion syndrome?

Answer 10

• Unexplained developmental delay or autism spectrum disorder
• Congenital anomalies/Dysmorphic features
• Suspected deletion or duplication syndrome

Question 11

Describe large deletion syndromes

Answer 11

• 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

Question 12

Descr8be small deletions

Answer 12

Smaller than 4 Mb may not be detected by standard karyotype, called “Microdeletion”

Question 13

Summarize Microdeletion syndromes

Answer 13

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

Question 14

Summarize microarray CGH

Answer 14

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))

Question 15

What are the steps in microarray CGH?

Answer 15

1. Label DNA with different fluorescent dyes
2. 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

Question 16

What causes Cri-du-chat syndrome?

Answer 16

Deletion of chromosome 5p
-cru-di-chat syndrome

46, XX,del(5)(p15.3)(pter) or 46,XY,del(5)(p15.3)(pter)

Question 17

What are the featuresof Cri-du-chat syndrome?

Answer 17

• High pitched, cat-like cry
• Micrognathia which influences the cat-like cry and later, speech problems
• Severe intellectual disability
• Microcephaly
• Hypertelorism (widely spaced eyes)

Question 18

What are the Cri-du chat syndrome diagnostic tests ?

Answer 18

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

Question 19

What is 22q11.2 deletion syndrome ?

Answer 19

Aka velocardiofacial syndrome or DiGeorge

Most contiguous gene (Microdeletion) disorder in humans, about 1:4000 to 1:6000

Question 20

What are the features of microdeletion of chromosome 22q11.2?

Answer 20

• 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

Question 21

What is Wolf-Hirschhorn syndrome?

Answer 21

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

Angelman syndrome is due to deletion of maternally chromosome 15q11-13 which includes the UBE3A gene

Question 22

What. Happens in chromosome 15q11-13 under normal conditions ?

Answer 22

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)

Question 23

What syndrome results from paternal deletion of SNRPN ?

Answer 23

Prader Willi syndrome

Question 24

What syndrome results from deletion in a UBE3A gene?

Answer 24

Angelman syndrome

Question 25

Contrast Prader- Willis syndrome and Angelman syndrome symptoms

Answer 25

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

Question 26

What May cause uniparental disomy?

Answer 26

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

Question 27

What are the two theories of uniparental disomy?

Answer 27

1. Trisomy rescue | 2. Chromosome reduplication

Question 28

What are inversions?

Answer 28

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

Question 29

What is the effect of inversions during crossover in meiosis ?

Answer 29

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

Question 30

What are isochromosomes?

Answer 30

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

Question 31

What is the X-isochromosome i(X)?

Answer 31

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

Question 32

What are ring chromosomes?

Answer 32

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