9 Cytogenetics II

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  1. Cri-du-chat Syndrome (5p-syndrome)
    • caused by a deletion of the terminal part of chromosome 5
    • • can detect using cytogenetics or FISH
  2. What are the symptoms of Cri-du-chat Syndrome?
    • • ocular hypertelorism (widely spaced eyes)
    • • mental retardation
    • • round face
    • • pointy ears
    • • epicanthal folds (skin fold of the upper eyelid covering the inner angle of the eye)
    • • microcephaly (smaller head)
    • • developmental & behavioral problems
    • • seizures
  3. Microdeletion Syndromes
    • • are often the result of a submicroscopic deletion of more than 1 gene from the chromosome; this can happen because multiple genes are physically contiguous on the chromosome
    • • the bigger the deletion, the worse the syndrome
    • • phenotype correlates with specific genes lost
    • • most often sporadic, but can be dominant
    • • deletion is too small to be seen by conventional karyotype analysis
    • • often need FISH to detect
    • • many are identified before the genes involved where known
  4. Examples of Microdeletion Syndromes (5):
    • • 7: Williams (elastin gene deleted)
    • • 15: Angelman
    • • 15: Prader Willi
    • • 17: Miller-Dieker (lissencephaly)
    • • 22: DiGeorge Velo-Cardio-Facial Syndrome
  5. What is DiGeorge Velo-Cardio-Facial Syndrome (chromosome 22 microdeletion) associated with?
    a lower number of T cells, so recurrent infection can be a problem
  6. DiGeorge Velo-Cardio-Facial Syndrome (DiGeorge VCFS)
    • • chromosome 22 microdeletion
    • • longer face
    • • smaller eyes
    • • prominent nasal roots
    • • small chin
    • • one way to pick up on dysmorphology is that children may not look like other members of their family
    • (also born with cleft palates & heart disease, abnormal kidneys, learning disabilities)
  7. Williams Syndrome
    • • microdeletion of elastin gene on chromosome 7
    • • children tend to be small, have ‘cocktail party’ personality
  8. Miller-Dieker Syndrome
    • • chromosome 17 microdeletion
    • • lissencephaly: lack of development of brain folds/grooves
    • • vertical forehead crease
  9. Deletions on which chromosomes exhibit syndromes? (7)
    4, 5, 8, 13, 15, 17, 18
  10. What test can be used to screen people for deletions (microdeletions) or duplications too small to be detected by a conventional karyotype?
    • a Comparative Genomic Hybridization (CGH) by microarray
    • • can test known syndromes caused by deletions/duplications of chromosome in one single sample
    • • microarray will screen entire genome for deletions/duplications too small to be detected by conventional karyotype
  11. Deletion v. Duplication
    • • loss of material (deletions) tend to result in a MORE severe phenotype than duplication of material
    • • most deletions are small, less than one chromosome band
  12. Comparative Genomic Hybridization (CGH) Array
    • • test DNA labeled in one color (green), while reference DNA is labeled using another color (red)
    • • mix them together & run them over the microarray
    • • green = gain of genomic material, red = loss of genomic material, yellow = balanced status (equal amounts of test & reference DNA)
  13. Translocations
    • the exchange of material between 2 or more chromosomes; can be balanced (reciprocal) or unbalanced
    • • balanced maybe identified by chance
    • • unbalanced translocation results in a combination of monosomy & trisomy - going to be missing one piece but have too much of another piece
  14. Infertility
    a year of unprotected sex with no conception

    • balanced translocations tend to be picked up in adulthood during something like a fertility screening
  15. Derivative Chromosome
    refers to the chromosome structurally rearranged by a translocation

    • this is the chromosome that HAS a deletion [monosomy] (& usually the ‘extra' part of the other chromosome with which the translocation occurred)
  16. Chromosomal Band Assignment
    • • ISCN assigned a number to each band of each chromosome based on landmarks
    • • the larger the band number, the further out from the centromere the band is
  17. notation example of an unbalanced translocation: 46,XX,der(8)t(1;8)(p22;q24)
    • • notates BOTH der [derivative chromosome] & t [translocation] → abnormal
    • • “der” chromosome is the one experiencing monosomy - it’s the chromosome that has the translocation added TO it

    *someone with a balanced translocation is at risk for having a fetus with an UNbalanced translocation because his or her 2 derivative chromosomes could go to different daughter cells in meiosis
  18. notation example of an balanced translocation:
    46,XX,t(1;8)(p22;q24)

    • only notates the t [translocation]
  19. q = ___________ and p = ___________
    • q = the long arm
    • p = the short arm
  20. 46,XY,t(3;5)(q21;p13)
    • • there is a balanced translocation between chromosomes 3 & 5
    • • 3 was broken in the long arm (place 21) & now has 5's part of the short arm 13 there
    • • 5 was broken in the short arm (place 13) & now has part of 3's long arm there
  21. 46,XX,der(3)t(3;5)(q21;p13)
    • • unbalanced translocation showing chromosome 3 broke in the long arm at position 21, & now contains chromosome 5's short arm 13 segment there
    • • chromosome 3 has monosomy (derivative)
    • • chromosome 5 has trisomy
  22. 46,XY,der(5)t(3;5)(q21;p13)
    • unbalanced translocation showing chromosomes 5 broke at position 13 on the short arm, & now contains some of the long arm of chromosome 3 at the break instead
  23. What are the majority of translocations?
    • FAMILIAL: present at birth in some or all of the cells in the body (constitutional)
    • • most are unique to a single family
  24. To date what are the 3 constitutional recurrent translocations that’ve been described?
    • • t(11;22)(q23;q11.2)
    • • t(4;8)(p16;p23)
    • • t(4;11)(p16.2;p15.4)
    • • found in completely independent families
  25. Robertsonian Translocations
    • • non-critical loss of genes in the short (p) arm regions of acrocentric chromosomes (13, 14, 15, 21, 22)
    • • chromosomes break at centromeres & long arms fuse to form a single chromosome with a single centromere
    • • short arms also join to form a reciprocal product: this usually contains nonessential genes & is lost within a few cell divisions
    • • usually fine until someone who has one wants to have children - mothers with R.translocations are at a higher risk of having a child who has a trisomy involving one of the translocated chromosomes than fathers
  26. Acrocentric Chromosomes
    • chromosomes 13, 14, 15, 21, & 22 have p arms that contain genetic material (eg. repeated sequences such as nucleolar organizing regions or rRNA genes) that can be lost without causing significant harm
    • • nobody who’s lost ribosomal RNA genes has been found to have an abnormal phenotype
  27. Robertsonian Translocation Notation:
    • 45,XX,der(13;14)(q10;q10)
    • • the long arm of 13 is joined to the long arm of 14
    • • 45 is NORMAL in Robertsonian (46 is NOT)
    • • q10 means the break is in the centromere & the long arm is present
  28. how Robertsonian translocation can result in trisomy during conception:
    • 46,XX,der(14;21)(q10;q10),+21
    • • a child inherits the translocated chromosome from one parent in addition to 2 normal copies from the other
  29. X-inactivation
    • • the choice between which X is inactivated is random if both chromosomes are normal
    • • if there’s an abnormal X, it is inactivated if it has the x-inactivation site on it (XIST region)
    • • if there is a translocation between the X chromosome & an autosome, the normal X is inactivated to preserve autosomal material
    • • if there is an unbalanced X translocation, the abnormal X is inactivated
  30. Inversion
    • • come in 2 types -
    • 1. pericentric: around centromere (p & q breakpoints) [peri = around] - piece rotates & changes orientation
    • 2. paracentric: occurs within the same chromosome arm, so outside the centromere (p & p or q & q)
    • • constitutional inversions have no impact on phenotype [eg. inv(5)(p13q13)] - they have to be stable otherwise they’d die out
  31. Disease Related Inversions
    • • inversions in some cells of your bone marrow can be diagnostic of leukemia - eg. inversion in long arm of chromosome 3
    • • she lists chromosomes 3, 14, & 16 as having disease related inversions
  32. Acquired Changes
    • • cancer is associated with genetic change & is often seen as a change in karyotype
    • • changes occur only in the organ affected (bone marrow in leukemia)
    • • not present at birth
    • • patient’s phenotype (appearance) is unchanged by any cancer associated translocation
  33. Philadelphia Translocation t(9;22)(q34;q11.2)
    • balanced translocation between 9 & 22; seen in CML (chronic myeloid leukemia)
    • • the der(22) was termed the Philadelphia chromosome
    • • is seen in 90-95% of cases of chronic myeloid leukemia (CML)
    • • one of the quickest ways to find the translocation is to do FISH
  34. Chronic Myelogenous Leukemia (CML)
    • • increased + unregulated growth of myeloid cells in bone marrow → accumulation of these cells in the blood
    • • cellular oncogene activation because of chromosomal translocation in stem cells between the long arms of chromosomes 9 & 22 (Ph [philadelphia chromosome])
  35. BCR-ABL Fusion Gene
    • a tyrosine kinase that activates a cascade of proteins that speed up cell division & inhibit DNA repair
    • • this makes the gene susceptible to further damaging mutations
    • • ABL oncogene = on chromosome 9
    • • BCR (breakpoint cluster region) = on chromosome 22
  36. Clonal Evolution
    • • additional karyotype changes (mutations) in an individual; usually occurs when there is disease progression
    • • as changes get more complex, unbalanced translocations become more frequent
    • • these only affect cells in the bone marrow; patient’s phenotype is unchanged

Card Set Information

Author:
mse263
ID:
323204
Filename:
9 Cytogenetics II
Updated:
2016-09-22 02:12:13
Tags:
MedFoundationsI Genetics Exam2
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MedFoundationsI,Genetics
Description:
Genetics Exam 2
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