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MedGen > Structural Rearrangements > Flashcards

Structural Rearrangements Flashcards

1
Q

What % of patients with ID and/or autism have a structural rearrangment?

A

15-20%

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2
Q

What’s the incidence of structural abnormalities in live births? conceptions? compared to numerical abn?

A

1:400 live birth
1:200 conceptions
less than
1:300 live births
1:13 conceptions

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3
Q

Which change is more difficult to detect? Structural or numerical?

A

structural

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4
Q

What meiosis are structural abn more likely to occur in?

A

male meiosis

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5
Q

What % of de novo, non-recurrent cytogenetically visible interstitial deletions are paternal in origin?

A

84%

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6
Q

What % of de novo, non-recurrent cytogenetically visible terminal deletions are paternal in origin?

A

70%

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7
Q

What % of de novo, non-recurrent cytogenetically visible deletions are paternal in origin?

A

58%

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8
Q

What % of de novo, non-recurrent cytogenetically visible translocations are paternal in origin?

A

62%

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9
Q

What % of de novo, non-recurrent cytogenetically visible reciprocal translocations are paternal in origin? What are they associated with?

A

96%

increased paternal age

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10
Q

Why is accurate genetic counseling for structural rearrangements difficult?

A

usually unique to a family
typically no identical cases in literature
typically empiric data is of limited use

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11
Q

What should we consider to provide accurate counseling for structural rearrangements?

A

chromosome region(s) involved

amount of imbalance(s)

family hx (abn live-born children, miscarriages, infertility)

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12
Q

What’s the recurrence risk for numerical abn in the mid 30s?

A

about 1%

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13
Q

What’s the recurrence risk for structural abn?

A

<1% to 50%

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14
Q

What’s the recurrence risk for those that carry homologous Robertsonian translocations?

A

100%

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15
Q

What type of rearrangements occurs when the long arms of 2 acrocentric chromosomes join to form a single metacentric or submetacentric chromosome?

A

Robertsonian translocation

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16
Q

What’s the prevlance of a Robertsonian translocation?

A

roughly 1:1000

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17
Q

What chromosomes can form a Robertsonian translocation?

A

13, 14, 15, 21, 22

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18
Q

What are the two most common Robertsonian translocations?

A

der or rob(13;14)(q10;q10): 75-85%

der or rob(14;21)(q10;q10): 8-10%

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19
Q

What are the rarest Robertsonian translocations? These are usually:

A

homologous (13;13)

de novo events

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20
Q

Why is der(14;21)(q10;q10) more clinically relevant than der(13;14)(q10;q10)?

A

Down syndrome is more survivable than trisomy 13

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21
Q

How many chromosomes are present in the karyotype of someone with a balanced Robertsonian?

A

45

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22
Q

What type of rearrangement involves the exchange of genetic material between non-homologous chromosomes or between homologous chromosomes at non-homologous sites?

A

reciprocal translocations

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23
Q

What’s the prevalence of reciprocal translocations?

A

1:700-1:1000

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24
Q

Roughly how many reciprocal translocations are inherited?

A

70%

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25
Q

If a structural rearrangement is observed, what testing should we always recommend? why?

A

parental chromosomes

whether it is inherited or de novo (increased risk) determines the risks

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26
Q

What % of reciprocal translocations are de novo?

A

30%

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27
Q

What are some reasons a de novo rearrangement is associated with risks even if it appears balanced?

A

it may not be truly balanced

the expression of a critical gene may be altered

there’s no FHx to draw information about impact

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28
Q

Small distal segments of translocation lead to ______ risks for clinically affected children. Why?

A

large

they lead to small imbalances

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29
Q

Large distal segments of translocation lead to ______ risks for clinically affected children. Why?

A

low

these are often not compatible with life and lead to high risks for miscarriage and/or periods of infertility

30
Q

Are monosomies or trisomies typically more detrimental?

A

monosomies

31
Q

Unbalanced translocations will result in what of each involved chromosome?

A

partial monosomy or trisomy

32
Q

What partial trisomies seen with unbalanced translocations are likely to be compatible with life?

A

chr 8, 9, 13, 18, 21, X, and Y

33
Q

What partial monosomies seen with unbalanced translocations are likely to be compatible with life?

A

4p, 5p, X, Y

34
Q

What partial trisomies and monosomies seen with unbalanced translocations are rarely compatible with life? What are we more likely to see with these?

A

14, 17, 19

miscarriages and periods of infertility are more likely

35
Q

What’s the empiric risk of having an unbalanced liveborn offspring for someone with a previous child or family member w/ an unbalanced rearrangement?

A

20-25%

36
Q

What’s the empiric risk of having an unbalanced liveborn offspring for someone with multiple miscarriages but no liveborn unbalanced individuals in their family?

A

2-4%

37
Q

What’s the empiric risk of having an unbalanced liveborn offspring for someone accidentally ascertained? How might this risk be modified?

A

4-5%

can be modified by how many generations the translocation has been segregating

38
Q

What should we offer for people that have been identified to have a balanced translocation? what’s their risk of having an unbalanced liveborn child?

A

prenatal testing

10-15%

39
Q

How can we derive more accurate estimate of reproductive risk for known translocations?

A

FHx
size of exchanged segments
chromosome regions involved

40
Q

How many breakpoints are present in inversions? how many are inherited?

A

2

80-90%

41
Q

In what type of inversion is centromere position and banding pattern altered?

A

pericentric

42
Q

What type of inversion is the change confined to a single arm? is the banding pattern altered?

A

paracentric

it can be altered

43
Q

What causes duplication-deficiency chromosomes?

A

an odd number of crossovers with a pericentric inversion

44
Q

What material is exchanged between homologous chromosomes if one carries an inversion?

A

the material distal to the inversion breakpoints

45
Q

Do large or small pericentric inversions create the highest risk for a liveborn abnormal child? why?

A

large

small distal segments can produce small imbalances

the further apart the breakpoints are, the more likely crossovers will occur between them and form duplication-deficiency chromosomes

46
Q

What are the empiric reproductive risks associated with pericentric inversions (2)? What should we do if one is identified?

A

5-15% if found through abn child

1% if ascertained fortuitously

we should offer prenatal testing for all pregnancies

47
Q

What types of unbalanced recombinant chromosomes result from paracentric inversions? W/ odd or even # of crossovers?

A

dicentric or acentric

odd

48
Q

What’s the estimated incidence of paracentric inversions?

A

0.09-0.49:1000

49
Q

What are the empiric reproductive risks associated with paracentric inversions? When have recombinants been seen?

A

0.1-0.5%

secondary to U-loop exchanges

50
Q

What type of rearrangement involves 3 breakpoints where a piece of chromosomal material is excised from one location and inserted a new location?

A

insertions

51
Q

What’s the prevalence of microscopically visible insertions?

A

1:80,000-1:10,000

52
Q

What’s the difference between intra- and interchromosomal insertions?

A

intra: all 3 breakpoints are in the same chr
inter: material is excised from one chr and inserted into another

53
Q

What can a single crossover event produce from an intrachromosomal insertion? what’s the general risk of having a child with an abn recombinant?

A

duplication or deletion chromosome

roughly 15%

54
Q

How can ring chromosomes exist? what would each of these result in?

A

replace normal chromosomes -> partial monosomy

be extra (supernumerary) -> partial trisomy

55
Q

How do ring chromosomes occur?

A

typically de novo events that form when a chromosome undergoes 2 breaks and the broken ends reunite to form a ring

56
Q

What are the most common rings?

A

13 and 18

57
Q

What phenotype is often associated with ring syndrome?

A

severe growth restriction without major malformations

58
Q

What is common in patients with rings? why?

A

mosaicism

dynamic mosaicism (more common in larger rings) due to their mitotic instability

59
Q

What types of things should we consider when a Robertsonian translocation is found?

A

unbalanced offspring, miscarriages/infertility, or UPD

60
Q

What chromosomes capable of forming Robertsonians are also associated with UPD? conditions?

A

chr 14 and 15

14:

  • mat: Temple syndrome
  • pat: Wang or Kagami-Ogata syndrome

15:

  • mat: Prader-Willi syndromw
  • pat: Angelman syndrome
61
Q

When is testing for UPD recommended?

A

1) fetus with a balaned Rob translocation involving chr 14 or 15
2) clinicallt abn infants or children who carry balanced Rob invovled 14 or 15
3) clinically abn children with normal karyotypes who have a parent with a Rob translocation with 14 or 15

62
Q

What structures do balanced translocation chromosomes for during meiosis?

A

quadrivalents

63
Q

What are the different ways quadrivalents can segregate?

A

alternate

adjacent-1

adjacent-2

64
Q

What type of segregation must occur for normal or balanced gametes to be produced in someone with a balanced translocation?

A

alternate

65
Q

What are the result(s) of adjacent-1 or adjacent-2 segregation in someone with a balanced translocation?

A

partial monosomy _____ and partial trisomy ______.

66
Q

What’s the most likely type of segregation in those with balanced translocations? second most common?

A

alternate

adjacent-1

67
Q

What type of segregation for balanced translocations is typically lethal?

A

adjacent-2

68
Q

When do we typically observe 3:1 segregants? what do they lead to?

A

translocations involving chromosomes with small p arms

small imbalances and the acrocentrics, chr 9 and 18

69
Q

Monosomy 1p is a common cause of:

A

intellectual disability

70
Q

What do inverted homologues form during meiosis I?

A

inversion loops

71
Q

What can be signs of dynamic mosaicism associated with ring chromosomes?

A

skin pigmentation and reduced growth

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