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Flashcards in Cytogenetics and Learning Disorders Deck (73):
1

What percentage of people with learning disorders have a cytogenetic abnormality?

About 16%

2

What % of unselected newborns have a cytogenetic abnormality?

About 1%

3

What is better tolerate by humans? Loss or gain of autosomal material?

Gain of chromosomal material is better tolerated by humans.

4

Which 3 autosomal trisomy syndromes are viable to term in non-mosaic form?

1). Trisomy 21 - Down syndrome
2). Trisomy 13 - Patau syndrome
3). Trisomy 18 - Edwards syndrome

5

What trisomies (other than trisomy 21, 13 and 18) may be viable in mosaic form?

Mosaic trisomy 8 and 9.

6

Are any autosome monosomies viable at term?

No autosome monosomy is viable at term and very few are detected even in pregnancy loss.

7

What is the most common trisomy seen in early spontaneous miscarriage?

Trisomy 16.

8

Describe the genetic mechanisms that lead to the conception of a child with Down syndrome.

Down syndrome is the most common genetic cause of mental retardation. 94% of Down syndrome individuals are trisomy 21 (47,XX or XY,+21). The majority of these cases arise through non-disjunction at maternal meiotic 1st division.

About 4% of Down syndrome cases arise due to an unbalanced 'robertsonian translocation'. This may be inherited from a balanced robertsonian carrier parent or may even arise de novo.

About 2% of cases of Down syndrome are mosaic. There arise due to post-zygotic mitotic non-disjunction events.

9

In very simple terms what happens when non-disjunction occurs?

The chromosome pairs do not segregate into the daughter cells evenly and so you can end up with disomic and nullisomic daughter cells. The disomic daughter cells that form disomic gametes will lead to trisomy when the zygote forms.

10

How can a non-disjunction event at mitosis result in a trisomy or a monosomy?

In mitosis the chromosomes are duplicated. 2 chromosome pairs will be duplicated to 4 pairs etc. If non-disjunction takes place at mitosis then it is possible for a daughter cell with 3 chromosome pairs to form.

11

How does mosaicism usually arise in Down syndrome?

Mosaicism usually arises as a result of mitotic, post-zygotic, non-disjunction events.

This could also be a corrective event - also referred to as 'trisomy rescue' resulting in a cell line with a normal chromosome complement. Rescue events can lead to a normal embryo with a trisomic placenta and vice versa.

12

List the physical features of Down Syndrome.

- Flat facial profile - flattened nose
- Eyes (palpebral fissures) slant upwards with epicanthic folds
- Small ears
- Flat back of head (brachycephaly)
- Protruding tongue
- Bilateral single palmar crease
- Shorter than average with poor muscle tone
- Mild to moderate mental retardation
- Frequent autistic spectrum disorder
- Cardiac defects
- Increased risk of leukaemia particularly in childhood (may be transient leukaemia).

13

What usually causes Patau syndrome?

Trisomy 13 - 47,XX or XY,+13. The vast majority of these present as a non-disjunctional primary trisomy.

It can also present due to an unbalanced robertsonian translocation.

Vast majority arise de novo.

14

What are the general features of Patau syndrome?

- Severe mental retardation
- Microcephaly
- Polydactyly
- Holoprosencephaly - cleft palate, nose and eye anomalies
- Reduced life expectancy - 80% die within 1st year

15

What is the genetic cause of Edward syndrome?

95% are due to primary trisomy - 47,XX or XY, +18. Some also present as trisomy for 18q, sometimes in the form of an isochromosome.

16

What are the most common features seen in Edwards syndrome?

- Microcephaly
- Prominent occiput
- Micrognathia
- Hypertelorism
- Clenched hands
- Rocker bottom feet
- Heart defects
- Omphalocele (defects of the abdominal wall)
- Severely reduced life expectancy
- Very severe mental retardation

17

What are the most common features seen in mosaic trisomy 8?

- Mild to moderate mental retardation
- Deep plantar furrows - palms and soles of feet

18

What are the most common features seen in mosaic trisomy 9?

- Mental retardation
- Congenital heart disease
- Downturned corners of the mouth

19

How can you get trisomy for part of a chromosome?

You can get trisomy for part of a chromosome. A duplicated segment of chromosome may be either direct or inverted (mirror image). Duplicated material may also be inserted into another chromosome.

20

What is an ESAC or marker chromosome?

- Extra Small Additional Chromosomes
- Additional (supernumary) chromosomes are often termed marker chromosomes since the chromosome origin is unknown.
- Most marker chromosomes are small and will often be mosaic. Often rings or small structurally unstable forms.
- The clinical significance will be dependent on their genetic composition.
- C-banding, DA-DAPI and silver staining were traditionally used, as well as parental studies to determine their clinical significance.
- C-banding shows whether marker carries heterochromatin or euchromatin and thus whether it is likely to carry euchromatin or not.
- DA-DAPI and silver staining were used to establish whether the material was derived from an acrocentric chromosome. If silver staining material is present in a marker then that material represents the acrocentric short arms and they are known to be non-coding.

21

What does C-banding of marker chromosomes show?

C-banding shows whether marker carries heterochromatin or euchromatin and thus whether it is likely to carry euchromatin or not.

22

What was DA-DAPI and silver staining used for?

- DA-DAPI and silver staining were used to establish whether the material was derived from an acrocentric chromosome. If silver staining material is present in a marker then that material represents the acrocentric short arms and they are known to be non-coding.

23

What is Pallister Killian syndrome? In what cells may Pallister Killian syndrome be detected?

Pallister Killian syndrome is associated with mosaicism for an additional isochromosome consisting of 2 copies of 12p (resulting in tetrasomy for 12p in the cells that carry the isochromosome).

It is often expressed in a tissue specific way and is rarely seen in metaphase preparations from blood.

May be detected in metaphase from skin cells or other tissues and is often detectable by FISH in interphase cells in the blood.

24

In what cells may Pallister Killian syndrome be detected?

The 12p isochromosome is often expressed in a tissue specific way and is rarely seen in metaphase preparations from blood.

May be detected in metaphase from skin cells or other tissues and is often detectable by FISH in interphase cells in the blood.

25

What are the most common features associated with Pallister Killian syndrome?

- Mental retardation
- Epilepsy
- Hypotinia
- Hypo- and Hyperpigmented patches of skin
- Distinctive (coarse) facial features including high forehead, sparse hair, hypertelorism, epicanthal folds and a flat nose.

26

What causes Cat-Eye syndrome?

Cat-Eye syndrome is associated with mosaicism for an additional small isochromosome consisting of 2 copies of the proximal part of 22q.

27

Describe the main features that are associated with Cat-Eye syndrome.

- Often tissue specific.
- Verticle colobomas in the eye (hence cat eye).
- Mild to moderat mental retardation.

28

What mosaic ESACs are associated with syndromes other than isochromosome 12p (in Pallister Kallian syndrome) and isochromosome 22q (in Cat-Eye syndrome)?

Other mosaic ESACs associated with syndromes include:

- an isochromosome of the proximal region of 15q (+i(15)(q11)) - often appears as a bisatellited marker.
- an isochromosome of 5p (+i(5)(p10)).

Both are always mosaic and may be tissue specific.

29

What types of cytogenetic syndromes involve loss of genetic material?

1). Deletion syndromes (such as Cri-du-chat, Wolf Hirschhorn), Miller Dieker, Smith Magensis).
2). Microdeletion syndromes (such as Digeorge syndrome and Williams-Beuren syndrome).

30

List the most common deletion syndromes.

- Cri-du-chat
- Wolf Hirschhorn
- Miller Dieker
- Smith Magensis

31

List the most common microdeletion syndromes.

- Digeorge syndrome
- Williams-Beuren syndrome

32

What chromosomal abnormality is involved in Cri-du-chat syndrome?

del 5p

33

What are the main features of Cri-du-chat syndrome?

- del 5p
- High pitched cry in infants
- Microcephaly
- Poor muscle tone
- Mental retardation

34

What chromosomal abnormality is involved in Wolf Hirschhorn syndrome?

del 4p

35

What are the main features of Wolf Hirschhorn syndrome?

- del 4p
- Prominent forehead
- Hypertelorism
- Broad beaked nose
- Described as 'greek warrior helmet' features
- Severe mental retardation

36

Why is it always advisable to investigate the parents in cases of apparent terminal deletion?

Although apparent terminal deletion it is always advisable to investigate the parents. Might actually be present in the form of an unbalanced translocation with a balanced translocation in one of the parents.

37

What chromosome abnormality is involved in Miller-Dieker syndrome?

- del(17)(p13.3)
- Lis1 gene deleted

38

What are the most common features seen in Miller-Dieker syndrome?

- Lissencephaly - smooth brain with lack of gyri due to incomplete neuronal migration
- Severe mental retardation
- Seizures
- Reduced life expectancy

39

What chromosomal abnormality causes Smith Magenis syndrome?

- An interstitial deletion of proximal 17p.
- del(17)(p11.2p11.2)
- 4mb common deletion region

40

What are the features of Smith Magenis syndrome?

- An interstitial deletion of proximal 17p.
- del(17)(p11.2p11.2)
- 4mb common deletion region
- Behavioural problems - self harming, sleep disturbance
- Synophrys, broad, square face, deep-set eyes, full cheeks, prominent lower ja, mouth tends to turn upward with a full outward curving upper lip

41

How do many of the recurrent micro-deletion/duplication syndromes arise?

There are a number of recurrent micro-deletion and micro-duplication syndromes. Many of these arise as de novo events as the result of non-allelic homologous recombination (NAHR) events between regions of homology interspersed through the genome. These are polymorphic regions of low copy repeat (LCRs). The presence of two LCRs within close proximity will predispose to NAHR resulting in either deletion or duplication of the intervening sequence.

42

Give 2 examples of recurrent microdeletion syndromes.

1). Digeorge syndrome
2). Williams-Beuren syndrome

43

What chromosomal abnormality causes Digeorge syndrome?

- del(22)(q11.2q11.2)

- Reciprocal duplication for this region also exits.

44

What chromosomal abnormality causes Williams-Beuren syndrome?

- del(7)(q11.23q11.23)

- Reciprocal duplication for this region also exits.

45

What is the phenotype of Digeorge syndrome?

Variable phenotype including:
- Aortic arch defects
- Learning difficulties
- Hypocalcaemia

May be inherited from a phenotypically normal parent (because phenotype is so variable).

Carrier has a 50% risk of passing the deletion on.

46

What is the risk of a carrier passing the Digeorge syndrome deletion on?

Carrier has a 50% risk of passing the deletion on.

47

True or false. Digeorge syndrome can be inherited from a phenotypically normal parent.

True. Because the phenotype is so variable.

48

What is the phenotype of Williams-Beuren syndrome?

- Heart defects
- Elfin-like features
- 'Cocktail party' manner - very good a small talk
- Learning difficulties
- Hypercalcaemia

49

What are the possible outcomes of segregation of a balanced reciprocal translocation?

Segregation of a balanced reciprocal translocation can result in:
- normal/balanced products
- unbalanced products as a result of 2:2 (adjacent segregation)
- Unbalanced products as a result of 3:1 segregation (tertiary or interchange trisomy or very rarely monosomy)

50

What is the most common recurrent reciprocal translocation? Are there any viable unbalanced products recorded for this Translocation?

- The translocation t(11;22)(q23;q11) is the most common recurrent reciprocal translocation seen in more than 160 unrelated families.
- Only one viable unbalanced product has ever been recorded for this translocation.
- Viable unbalanced product is in the form of Emanuel Syndrome - 47, XX (or XY), +der(22),t(11;22)(q23.3q11.2).
- Emanuel syndrome is a tertiary trisomy with a gain of 22pter-22q11 and 11q23-11qter.
- The recurrence risk is higher in female balanced carriers (5-6%)
- Carriers have an increased risk of pregnancy loss.

51

What is the genetic cause of Emanuel syndrome?

- The translocation t(11;22)(q23;q11) is the most common recurrent reciprocal translocation seen in more than 160 unrelated families.
- Only one viable unbalanced product has ever been recorded for this translocation.
- Viable unbalanced product is in the form of Emanuel Syndrome - 47, XX (or XY), +der(22),t(11;22)(q23.3q11.2).
- Emanuel syndrome is a tertiary trisomy with a gain of 22pter-22q11 and 11q23-11qter.
- The recurrence risk is higher in female balanced carriers (5-6%)
- Carriers have an increased risk of pregnancy loss.

52

What are the clinical features of Emanuel syndrome?

Clinical features of patients with an additional der(22) include:
- mental retardation
- craniofacial abnormalities including deep set eyes, lower set ears and a longer upper lip
- congenital heart defects

53

What is meant by the term 'full' or 'primary' trisomy?

"Full trisomy", also called "primary trisomy", means that an entire extra chromosome has been copied. *"Partial trisomy" means that there is an extra copy of part of a chromosome.

54

What is meant by the term 'secondary' trisomy?

"Secondary trisomy" - the extra chromosome has quadruplicated arms (the arms are identical; it is an "isochromosome").

55

What is meant by the term 'tertiary' trisomy?

"Tertiary trisomy" - the extra chromosome is made up of copies of arms from two other chromosomes.

56

Give an example of a viable adjacent 1 segregant.

- The t(4;8)(p16;p23) is a recurrent reciprocal translocation.
- Both adjacent 1 segregancts from this translocation are viable.
- 46,XX or XY,der(4)t(4;8) - results in a Wolf Hirshhorn phenotype.
- 46,XX or XY,der(8)t(4;8) - associated with less specific features.

57

What phenotype is the 46,XX or XY,der(4)t(4;8) segregant of the t(4;8)(p16;p23) translocation associated with?

46,XX or XY,der(4)t(4;8) - results in a Wolf Hirshhorn phenotype.

58

What are 'priavate' chromosome rearrangements?

- Most reciprocal translocations arise as a 'private' rearrangement specific to a family.
- Where malsegregation has resulted in a live born unbalanced offspring the recurrence risk must be considered significant.
- Where no family history is available segregation analysis is allow an estimate of the risk to any future pregnancy.

59

Describe the basics of chromosome inversions.

- Inc centromere = Peri
- Exc centromere = Para
- Balanced inversion carriers are usually normal but may have reproductive problems
- There is a risk of having abnormal children if the inverted segment is big, includes the centromere, or if the end sections are very small

60

Under what conditions is the risk of having viable unbalanced offspring with LD highest for pericentric inversion carriers?

For pericentric inversion carriers the risk of viable unbalanced offspring with LD is highest if the non-inverted segments are small or non-coding (i.e. acrocentric short arms).

61

What is the approximate risk of a paracentric inversion carrier having an unbalanced liveborn as the result of recombination of the inversion?

For paracentric inverison carriers the risk of an unbalanced liveborn as the result of recombination of the inversion is negligible.

62

How do pericentric inversions behave at meiosis? If recombination occurs within the inversion loop what may the outcomes be?

- An inversion loop forms when the chromosomes pair at meiosis. This forms because the inverted chromosome and the normal homologue are trying to pair along the length of the chromosome at meiosis and they can't just form a simple pair side by side because there would be segments that wouldn't pair up. They form a complex loop formation in order to keep the regions of homology next to each other.
- Recombination in the inversion loop gives either normal chromosomes, inverted chromosomes, recombinant chromosomes dup p distal, or recombinant chromosomes dup q distal.
- The more telomeric the breakpoints for the inversion are the higher the risk of viable imbalance (because on recombination you will get dup of the part of the chromosme beyond the break point - if it is small then may still be viable.

63

How do paracentric inversions behave at meiosis? If recombination occurs within the inversion loop what may the outcomes be?

- Like pericentric inversions also will form a loop at meiosis in order to bring the areas of homology into contact with one another.
- If recombination occurs in the inversion loop then this may result in a normal chromosome, an inverted chromosome, a dicentric recombinant chromosome, or an acentric recombinant chromosome.
- Acentric fragments will be lost at the next mitotic division.
- Dicentric fragments tend to get pulled apart and lost during mitotic divisions.

64

Why do paracentric inversions have a negligible risk of producing live born imbalanced offspring?

- If recombination occurs in the inversion loop then this may result in a normal chromosome, an inverted chromosome, a dicentric recombinant chromosome, or an acentric recombinant chromosome.
- Acentric fragments will be lost at the next mitotic division.
- Dicentric fragments tend to get pulled apart and lost during mitotic divisions.
- Therefore, the unbalanced chromosome outcomes of recombination rarely survive mitotic division.

65

Why are pericentric inversions involving the p arm of acrocentric chromosomes likely to result in viable recombinants?

Because the p arm of acrocentric chromosome is non-coding.

66

What is meant by the term 'insertional translocation'? What are the 2 different types of chromosomal translocation?

1). Insertion is where a segment from one chromosome is inserted into a different chromosome (interchromosomal insertion).
2). Where a segment from one chromosome is inserted into a different place within the same chromosome (intrachromosomal insertion).

67

What is an interchromosomal insertion?

Where a segment from one chromosome is inserted into a different chromosome (interchromosomal insertion).

68

What is an intrachromosomal insertion?

Where a segment from one chromosome is inserted into a different place within the same chromosome (intrachromosomal insertion).

69

What determines the risk of imbalance for an insertion?

- The risk of a viable imbalance for a balanced insertion will depend on the size and the gene content of the inserted segment.
- As a rule of thumb the risk of an insertion carrier is generally higher than for a translocation carrier because the unbalanced form consists of either a gain or loss, not a compound of both.
- For an intrachromosomal insertion the risk will also depend on the distance between the location of the inserted material and where it came from because there has to be a recombination event between those two points in order to result in a partial trisomy (gain) or a partial monosomy (loss).

70

Are translocation carriers or inversion carriers at a higher risk of producing abnormal viable offspring?

As a rule of thumb the risk of an insertion carrier is generally higher than for a translocation carrier because the unbalanced form consists of either a gain or loss, not a compound of both.

71

What is a ring chromosome? What categories to ring chromosomes fall into?

- A ring chromosome is formed from a single chromosome with loss of materials from, and then fusion of, the p and q arms.
- Ring chromosomes fall into 2 categories:
1). Large ring chromosomes - little material deleted, in place of notmal chromsome (e.g. 46,XX,r(4))
2). Additional ring chromsomes - often small ESACs or markers, e.g. 47,XX,+r

72

What problems may be encountered with ring chromosomes at meiosis?

Ring chromsomes are subject to frequent errors at meiotic division and the presence of a ring chromosome can result in dynamic mosaicism (a mosaicism that is caused each time the cells go through normal mitotic division). This can result in cells with loss of the ring, additional copies of the ring and double size rings.

73

Describe the features of generalised ring chromosome syndrome.

- Associated with large rings replacing a normal homologue.
- Growth restrictions/short stature with or without LD. This results from the dynamic mosaicism associated with rings during cell division. Any cells generated from a mis-division with a complete monosomy for a particular autosome are likely to be inviable.
- Other clinical features will be dependant on the size and genetic content of the deleted segments.