9 Cytogenetics II

• caused by a deletion of the terminal part of chromosome 5
• • can detect using cytogenetics or FISH

• • 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

• • 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

• • 7: Williams (elastin gene deleted)
• • 15: Angelman
• • 15: Prader Willi
• • 17: Miller-Dieker (lissencephaly)
• • 22: DiGeorge Velo-Cardio-Facial Syndrome

a lower number of T cells, so recurrent infection can be a problem

• • 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)

• • microdeletion of elastin gene on chromosome 7
• • children tend to be small, have ‘cocktail party’ personality

• • chromosome 17 microdeletion
• • lissencephaly: lack of development of brain folds/grooves
• • vertical forehead crease

4, 5, 8, 13, 15, 17, 18

• 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

• • 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

• • 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)

• 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

a year of unprotected sex with no conception

• balanced translocations tend to be picked up in adulthood during something like a fertility screening

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)

• • 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

• • 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

46,XX,t(1;8)(p22;q24)

• only notates the t [translocation]

• q = the long arm
• p = the short arm

• • 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

• • 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

• 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

• FAMILIAL: present at birth in some or all of the cells in the body (constitutional)
• • most are unique to a single family

• • t(11;22)(q23;q11.2)
• • t(4;8)(p16;p23)
• • t(4;11)(p16.2;p15.4)
• • found in completely independent families

• • 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

• 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

• 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

• 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

• • 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

• • 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

• • 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

• • 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

• 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

• • 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])

• 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

• • 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