Structural Chromo Abnormalities

Question 1

Chromo rearrangements require?

Answer 1

2 DSBs, can be induced by a variety of damaging agents (ionizing radiation etc.)
Necessary for meiotic recombination

Question 2

2 types of structural rearrangements

Answer 2

1. ) Balanced
   a. inversions
   b. reciprocal translocation (para or pericentric)
   c. robertsonian translocation
2. ) Unbalanced
   a. Deletion
   b. Duplication
   c. Ring chromosome
   d. Isochromosome

Question 3

Balanced rearrangements?

Answer 3

NO LOSS of genetic material. But have varying stabilities.

Question 4

Inversion

Answer 4

One chromos has 2 DSBs and intervening sequence is inverted before rejoining.
Paracentric: exclude centromere
Pericentric: include centromere
These inverted chromos may have NORMAL genetic complements, so could have no phenotype, but can lead to meiotic abnormalities.

Question 5

How does inversion lead to issues w/ meiosis?

Answer 5

During pairing of homologs, a loop happens (b/c you want to line up homologous sequences).
If cross-over occurs in this inverted region of a PARACENTRIC inversion, both dicentric (2 centromeres) and acentric chromos can be generated (leading to chromo loss or breakage).

In PERICENTRIC inversions, cross-overs in inverted region can lead to duplications and deletions. Ex: 46,XX,inv(9)(p13q13)

Question 6

Reciprocal translocation

Answer 6

Results from breakage and rejoining of non-homologous chromos, with reciprocal exchange of broken segment.

Question 7

Reciprocal translocation and meiosis

Answer 7

Carriers have a higher risk of producing unbalanced gametes (often found in couples with spontaneous abortions/infertile males).
When pairing in meiosis, form a QUADRIVALENT figure. Can segregate: alternate, adjacent-1, adjacent-2.

Question 8

alternate, adjacent-1, adjacent-2.

Answer 8

Alternate: most frequent, either get normal chromo complement or 2 reciprocal translocation chromos, both are balanced. FINE.
Adjacent 1 and 2 lead to unbalanced gametes. Partial monosomy or trisomy.
5-10% risk of lethality.
46,XX,t(9;22)(q34:q11.2)… translocation with chromo 9 and 22… causes CML.

Question 9

Robertsonian translocation

Answer 9

Fusion of 2 acrocentric chromos in centromeric regions, resulting in loss of both short arms (rDNA repeats).
They REDUCE the chromosome number, but are considered blanced.

Question 10

Offspring of robertsonian carriers?

Answer 10

Can result in unbalanced karyotypes, monosomies and trisomies.
Chromosome 14 is most common! 85%.
Ex: 45,XX,der(14q;21q) and 14 and 13 45,XX,der(13q;14q).

Seen as rob or der.

Question 11

Unbalanced

Answer 11

have additional or missing genetic info. Phenotypes probably abnormal.
Duplication of genetic material can cause partial trisomy after fertilization whereas deletions –> partial monosomy.

Question 12

Deletion

Answer 12

Loss of genetic info. From simple chromo breakage/rejoining, unequal crossing over b/w misaligned homologous chromos or sister chromatids, or abnormal segregation of a balanced translocation or inversion.

Terminal or interstitial (contains centromere, ring chromo from deleted seg).
Clinically causes haploinsufficiency.

Question 13

Cri-du-chat

Answer 13

46, XY, del(5)(p15) an example of deletion of chromo 5.

Question 14

Duplication

Answer 14

Gain of genetic info, generally less harmful than deletion, but may cause abnormalities (trisomy 21).

Can also happen from unequal crossing over by abnormal segregation during meiosis in a carrier of a translocation or inversion.

Question 15

Ring chromosome

Answer 15

Chromosome segment that circularizes and has kinetochore activity for stable transmission (also called marker chromosome)
46, XY, r(13)(p11q34).. male with ring chromo from p11-q34 region of chromo 13.

Question 16

Isochromosome

Answer 16

One arm is missing and other is duplicated in mirror-image fashion.
Occurs through exchange involving one arm of a chromosome and it’s homologue at the proximal edge of the arm, adjacent to the centromere.

Question 17

Down syndrome and isochromosomes

Answer 17

Most common is long arm of X (karyotype i(Xq))

Small # of down syndrome pts. have 21q21q isochromosomes (46,XX,i(21)(21q21q)). This is rare. But all gametes of carrier of this have either trisomy 21 or are inviable (monosome 21)!! so 100% of offspring are ABNORMAL.

Question 18

Abnormal segregation, unequal crossing over cause?

Answer 18

Deletions, duplications

Question 19

Who has a risk of unbalanced gametes?

Answer 19

Carriers of inversions (loop, crossing over issues), reciprocal translocations (quadrivalent figure, segregation issues)…. these lead to duplications and deletions in offspring.
isochromosomes (all abnormal gametes)

Question 20

Recurrence risk?

Answer 20

Often it is a random event and unlikely to recur (we do have in utero diagnosis), however sometimes it can be due to something parent is carrier and then the recurrence risk is increased (with isochromosome it’s 100%!).

Question 21

Continguous gene syndrome

Answer 21

Abnormal phenotypes caused by over-expression or loss (haploinsufficiency) of NEIGHBORING genes.
Most affect X chromo and males.
Duchennes is an example.

Question 22

Velocardiofacial syndrome

Answer 22

Del22q11
Cleft palate, septal defects.
Continguous gene syndrome.

Question 23

DiGeorge Syndrome

Answer 23

Del22q11. Continguous gene syndrome.

Neural crest issues, absent thymus and parathyroids, congenital heart disease.

Question 24

Charco-Marie Tooth Syndrome

Answer 24

Duplication of gene for myelin protein. Weakness of foot/lower leg muscles. Several forms (all affect fx. or peripheral n).
The deletion of this causes pressure palsy.