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Cri-du-chat Syndrome (5p-syndrome)
- caused by a deletion of the terminal part of chromosome 5
- • can detect using cytogenetics or FISH
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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
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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
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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
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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
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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)
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Williams Syndrome
- • microdeletion of elastin gene on chromosome 7
- • children tend to be small, have ‘cocktail party’ personality
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Miller-Dieker Syndrome
- • chromosome 17 microdeletion
- • lissencephaly: lack of development of brain folds/grooves
- • vertical forehead crease
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Deletions on which chromosomes exhibit syndromes? (7)
4, 5, 8, 13, 15, 17, 18
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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
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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
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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)
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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
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Infertility
a year of unprotected sex with no conception
• balanced translocations tend to be picked up in adulthood during something like a fertility screening
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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)
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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
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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
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notation example of an balanced translocation:
46,XX,t(1;8)(p22;q24)
• only notates the t [translocation]
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q = ___________ and p = ___________
- q = the long arm
- p = the short arm
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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])
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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
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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
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