Day 4, Lecture 2: Genetics V: Human Chromosome Abnormalities

Question 1

Clinical Cytogenetics

Answer 1

• Study of the relationship of chromosomal alterations and genetic diseases in human beings

Question 2

Chromosomal abnormalities cause

Answer 2

• Pregnancy loss
• Congenital malformations
• Intellectual disabilities (Mental Retardation)
• Play a role in the pathogenesis of malignancy

Question 3

How common are chromosome abnormalities

Answer 3

• about 1% of live births
• about 50% of first trimester miscarriages

Question 4

Classification of cytogenetic mutations

Answer 4

Question 5

Numerical Chromosome Abnormalities

Answer 5

Question 6

What is the most common chromosome abnormality seen in live births?

Answer 6

• Trisomy 21
• Incidence 1 out of every 691 live births
• Can happen to women of all ages, races and economic levels

Question 7

Causes of Trisomy 21

Answer 7

• Caused by having 3 compies of chromsome 21
  
  • 95% is nonfamilial Trisomy 21
  • 3-4% is unbalanced translation
    
    • only 1% are familial unbalanced translocation
  • 1-2% is mosaicism with two cell lines- normal and trisomy 21

Question 8

Common Aneuploidy Conditions

Answer 8

• Autosomes
  
  • Trisomy 21
  • Trisomy 18
  • Trisomy 13
• Sex Chromosomes
  
  • Monosomy X
  • Klinefelter Syndrome

Question 9

Clinical Features of Trisomy 21

Answer 9

Question 10

What is Mosaicism?

Answer 10

• The situation in which not all cells in an organism possess the same genotype. Mosaicism usually occurs as the result of postconceptional (acquired) changes.

Question 11

Trisomy 18 (Edwards Syndrome)

Answer 11

Question 12

Trisomy 13 (Patau Syndrome)

Answer 12

Question 13

Monosmy X (Turner Syndrome)

Answer 13

Question 14

Klinefelter Syndrome (47, XXY)

Answer 14

Question 15

Do Chromosome aneuploidy conditions usually run in families?

Answer 15

• No, it is a sporadic event

Question 16

Structural Abnormailities

Answer 16

Question 17

What is an Isochromosome?

Answer 17

One arm is duplicated forming two arms with a shared centromere

Question 18

Chromosomal Translocations

Answer 18

Question 19

Question 20

Question 21

Microdeletion Syndromes bridge the gap between

Answer 21

• Single gene and chromosomal syndromes
  
  • The deletion of a megabase or so is too small to be seen under the microscope, however, it may involve a dozen or more genes
  • FISH analysis and chromosome microarray are revealing increasing numbers of such submicroscopic chromosomal abnormalities

Question 22

Molecular pathology puts deletions/duplications into what three categories

Answer 22

Question 23

microdeletion syndromes, contiguous gene syndromes, and segmental aneuploidy are now generally referred to as

Answer 23

• Genome disorders
  
  • (note: Genome disorders have a complex phenotype (frequently includes mental retardation, developmental delay, and behavioral problems) due to alteration of gene dosage)
    
    • Haploinsufficiency
      
      • Deletion (majority of genome disorders)
      • Terminal deletion (telomeric)
      • Imprinting or UPD
    • Overexpression
      
      • Duplication (minority of genome disorders)

Question 24

Mechanism of genome disorders

Answer 24

• Usually less than 5Mb is involved in the deletion or duplication that leads to a genome disorder
• Areas of high recombination are often flanked by unique low copy repeats
• Due to the low copy repeats, the chromatids misalign during recombination in meiosis
• This misalignment leads to non-homologous recombination and unequal crossing-over

Question 25

Can a child inherit a microdeletion syndrome from a parent?

Answer 25

Yes

Question 26

Williams Syndrome

Answer 26

Question 27

Langer-Giedon Syndrome

Answer 27

Question 28

DiGeorge Syndrome

Answer 28

Question 29

Duplication 22q syndrome

Answer 29

Question 30

Prader-Willi Syndrome

Answer 30

Question 31

Angelman Syndrome

Answer 31

Question 32

Genetics of Prader-Willi/Angelman Sydrome

Answer 32

Question 33

1p36 Deletion Syndrome

Answer 33

Question 34

Cri-du-Chat Syndrome

Answer 34

Question 35

Wolf-Hirschorn Syndrome

Answer 35

Question 36

Smith-Magenis Syndrome

Answer 36

Question 37

Chromosome Analysis

Answer 37

Question 38

Karyotype

Answer 38

Question 39

Metacentric

Answer 39

* Centromere is central with arms being almost equal length

Question 40

Submetacentric

Answer 40

Off-centered centromere with arms being different lengths

Question 41

Acrocentric

Answer 41

Centromere is near one end

Question 42

Fluorescence in situ hybridization (FISH)

Answer 42

* Uses fluorescent probes that bind to only those parts of the chromosome indicated for study * Used to detect **microdeletion syndrome, aneuploidy, unknown chromosome material seen on karyotype**

Question 43

explain how FISH is able to show a deletion syndrome

Answer 43

* A chromosome reporter probe is able to show which chromosome you are looking for a deletion at * A critical region probe will attach if the genes are there and will not attach if they have been deleted (example in the picture)

Question 44

Chromosome Microarray analysis (aka Comparative genome hybridization (CGH))

Answer 44

* Genome-wide screening * used to measure the differences between two different DNA samples (control and test) in copy number, or dosage, of a particular DNA segment * Limitations: * Cannot detect balanced rearrangments * Cannot provide the physical location of copy-number variants of unkown clinical significance * Cannot detect low levels of mosaicism

Question 45

Specimen Types for Chromosome Analysis

Answer 45

* White blood cells in peripheral blood * preferred specimen type * Fibroblasts from skin biopsy * Solid tumor biopsy * Bone marrow * Fetal cell derived by * amniocytes from amniotic fluid * Collected via a procedure called amniocentesis * Chorionic villus cells * Collected via a procedure called chorionic villus sampling * Fetal blood * Collected via a procedure periumbilical blood sampling * Products of Conception

Question 46

Abbreviations used to describe chromosome and their abnormalities