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Genetics block 2 > Clinical cytogenetics: number and structure > Flashcards

Clinical cytogenetics: number and structure Flashcards

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1
Q

What is the clinical relevance of chromosome abnormalities?

A

major category of genetic disease and are a leading cause of congenital anomalies, intellectual disability, and pregancy loss

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2
Q

What causes abnormalities of chromosome number?

A

nondisjunction

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3
Q

Define nondisjuction. When can it occur?

A

error in cell division whereby improper segregation leads to abnormal chromosome number (monosomy or trisomy)

can occur in any cell division

  • meiosis I (age related risk of maternal MI nondisjunction)
  • Meiosis II
  • Mitosis => leading to mosaicism
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4
Q

What does mosaicism result from?

A

results from clonal expansion of the cell that first acquired the error

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5
Q

Define the terms wrt to chromosome number

  • euploid
  • aneuploid
  • polyploid
A
  • Euploid (=normal)
  • • Haploid (n=23) • Diploid (n=46)
  • Aneuploid
  • • Monosomy (n=45) • Trisomy (n=47)
  • Polyploid
  • • Triploidy(n=69) • Tetraploidy (n=92)
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6
Q

Describe polyploidy wrt chromsome sets, what causes it, how common, and result

A

One (or 2) complete set(s) of extra chromosomes

  • triploidy caused by fertilzation by two sperm (dispermy)
  • tetraploidy caused by failure of cell divsion

It is common at conception and common cause of spontaneous abortion

polyploidy is a nonviable entity

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7
Q

Describe how nondisjuction can involve any chromosome wrt autosomessex chromosomes, mosaicism

A
  • autosomes have limited viability
  • ALL monosomies are lethal while most trisomies are lethal (13, 18, 21)
  • Sex chromosomal aneuploidy is better tolerated compared to autosomes
  • must have at least one X for survival
  • Mosaicism is abnormal+normal cell lines
  • its phenotype is less severe
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8
Q

When are aneuploidies the most lethal wrt development?

A

preimplantation embryos so from week 0-6

these lead to pre-clinical abortions generally

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9
Q

What are the only viable aneuploidies?

A

13, 18, 21

XXX, XXY, XYY

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10
Q

What are characteristics of Down Syndrome (Trisomy 21)?

A
  • Mental retardation
  • flat facial profile
  • prominent epicanthal folds
  • simian crease
  • duodenal atresia (intestinal obstruction)
  • congenital heart defect
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11
Q

What is the etiology and incidence of trisomy 21?

A

Etiology

  • 95% nondisjunction, especially maternal meiosis I (47, XX +21 or 47, XY, +21)
  • 5% translocation

Incidence

  • 1-800 live births
  • significant risk of miscarriage and still birth but 20% survive to live birth
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12
Q

What are the clinical characteristics of Trisomy 18 (Edwards syndrome)? What is the life expectancy?

A
  • severe mental retardation
  • prenatal growth deficiency
  • congenital heart defect
  • rocker bottom feet
  • clenched hand

Life expectancy <1year

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13
Q

What is the karyotype, etiology and incidence rate of trisomy 18?

A

47, XX, +18 (or 47, XY, +18)

Etiology

maternal nondisjunction

Incidence

  • 1/6000 live births
  • <5% conceptions
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14
Q

Describe the clinical findings of Trisomy 13 or Pataue syndrome

A
  • abnormal development of midface, eye, forebrain
  • microphthalmia (close-set or fused eyes)
  • cleft lip/palate
  • holoproencephaly
  • polydactyly; syndactyly
  • congenital heart defect
  • severe mental retardation
  • very short life expectancy
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15
Q

What is the karyotype, etiology and incidence rate of Trisomy 13?

A

47, XX, +13 (or 47, XY, +13)

Etiology

  • 80% meiotic nondisjunction (maternal)
  • <20% robertsonian translocation involving chromosome 13
  • Rare : mosaicism or more complex abnormality of chromosome 13

Incidence

  • 1/10,000 live births
  • <5% conceptions survive to term
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16
Q

What is the survival ability of Trisomy 13?

A

mean survival is very limited; however, longer term survival has been reported

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17
Q

Describe the severity of different chromosome abnormalities

A

less severe phenotypes seen in sex chromosome abnormalities

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18
Q

What role does the X chromosome play in sex chromosome abnormalities?

A

There is a role of X inactivation (all but one X will be inactivated)

X chromosome nullisomy (no copy) is not viable

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19
Q

What is the incidence rate of sex chromosome abnormalities?

A
  • incidence of ALL sex chromosome abnormalities is 1/500 births
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20
Q

What are the clinical findings of Turner syndrome?

A
  • short stature
  • ovarian dysgenesis; primary amenorrhea
  • newborn lymphedema (swelling of hands/feet)
  • congenital heart defect
  • webbing of neck
  • prenatal: cystic hygroma
  • normal intelligence
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21
Q

What is the karyotype and etiology for turner syndrome?

A

45, X (and variants)

sole monosomy compatible with live birth

Etiology

  • 50% 45, X (meiotic nondisjunction, 80% of which is paternal)
  • 35% mosaic 45,X/46,XX (or 45,X/47,XXX or 45,X/46,X,i(Yq)
  • 5% mosaic with Y bearing cell line (45,X/46,XY or 45,X/46,X,i(Yq)
  • 10% structural abormalities of X chromosome (46,X,i(Xq)
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22
Q

****What are some paradoxes of Turner syndrome involving etiology and outcome?****

A

Etiology

  • mostly paternal nondisjunction (XY)
  • not associated with advanced maternal age

Outcome

  • incidence is 1-2% of conceptions along with the >99% fetal loss rate proposed role of confined placental mosaicism
  • 1/2500 female live births
  • _***Relatively mild phenotype in survivors***_
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23
Q

What are some of the clinical findings of Klinefelter syndrome? When is it diagnosed?

A
  • primary hypogonadism
  • tall with long extremities
  • gynecomastia (breast development)
  • reduced IQ (10-15 points)

Diagnosis is often subsequent to delayed puberty or infertility

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24
Q

What is the karyotype, etiology and incidence rate for Klinefelter syndrome?

A

47, XXY (85%) and 15% having mosaicism (46,XY/47,XXY) along with rare variants such as 48,XXXY

Etiology

  • 50% paternal nondisjunction (XY)
  • 50% maternal nondisjunction (maternal age effect

Incidence

  • 1/1000 male live births
  • 1/2 spontaneously aborted
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25
Q

What is the karyotype, etiology, and incidence of triple X syndrome? What are traits associated with this disease?

A

47,XXX (trisomy X)

Etiology

  • 90% maternal nondisjunction with age effect

Incidience

  • 1/1000 female live births

XXX children has an essentially normal phenotype with mild learning problems

Majority remain undiagnosed

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26
Q

Describe the etiology and incidence of 47, XYY syndrome. What are characteristics of the phenotype?

A

Etiology

paternal meiosis II nondisjunction (no age effect)

Incidence

1/1000 male live births

These patients have essentially normal phenotype which are normally tall with some educational and behavioral problems

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27
Q

Name the aneuploidies that are associated with maternal age-related risk of nondisjunction

A
  1. Trisomy 21
  2. trisomy 18
  3. trisomy 13
  4. 47, XXY
  5. 47, XXX
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28
Q

T/F most down syndrom babies are born to younger mothers

why?

A

true

many more babies are born to younger mothers so around 75% are born to mothers under 35

while mothers over 35 account for 9% of pregnancies and 25% of down syndrome babies

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29
Q

At what age do mothers get a higher risk for children with down syndrome? give rates of each

A

Age <30 => risk <1 in 1000

Age >40 => >1 in 100

Older mothers are at a higher risk which is seen drastically at age 30

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30
Q

What is FISH (fluoresence in situ hybridization)? How does it work, and what type of results are given?

A

specific probe applied to patient’s cells so FISH determines the number of copies present

The probe DNA hybridizes to complementary chromosomal DNA

Fluorescence microscopy used to visualize probe on chromosome

You should just count the dots to determine if it is normal or not

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31
Q

What is mosaicism and the 3 steps that must occur for cell line to get to its end results such as trisomy 21?

A

presence of more than 1 cell line

  1. ALWAYS involves post-zygotic error
  2. biology plays out and mitotic nondisjunction occurs
  3. ascertainment for the chromosomal cell line
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32
Q

Describe errors that occur in mosaicism

A
  • errors giving rise to mosaicism are random and unique
  • in general, error will be passed to all cell progeny via mitosis
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33
Q

Describe the abnormal cells wrt mosaicism

A

abnormal cell line may be at a selective disadvantage and may be eliminated

may be present in any proportion (low to high) which will correlate with the degree of severity

34
Q

How often is mosaicism diagnosed and why is diagnosis hampered?

A

mosaicism is encountered 1/300 amniocenteses

diagnosis is hampered by inherent limitations of sampling which includes tissue-specific differences

35
Q

What is a leading cause of intellectual disability and pregnancy loss?

A

abnormalities of chromosome structure are a significant category of genetic disease and leading cause of intellectual disability and pregnancy loss

36
Q

What are critically important in the causality, diagnosis, and treatment of many cancers?

A

constitutional abnormalities, acquired structural abnormalities

37
Q

What is chromosome classification based on? what are the 3 types?

A

both size and centromere position

metacentric, submetacentric, acrocentric

38
Q

What chromosomes can be associated with acrocentric classification? what is at the stalk of them?

A

chromosomes 13, 14, 15, 21, 22

rRNA genes are located in the stalks of acrocentric chromosomes

many tandem copies per chromosome

39
Q

describe structural abnormalities based on breakage and rearrangement of chromosome segments. What is the clinical significance?

A

visible rearrangements seen in the microscope as a deviation from the normal banding pattern

structural abnormalities involving very small segments may not be microscopically visible. submicroscoic abnormalities require molecular approaches for detection

Clinical significance

  • phenotypic abnormalities
  • reproductive risks
  • significance of acquired abnormalities in cancer
40
Q

chromosomes can undergo structural abnormalities can have improper repair of chromosome breaks. With this being said, what is required for chromosome stability?

A

one centromere and 2 terminal telomeres are required for chromosome stability

41
Q

Describe balanced and unbalanced structural abnormalities

A

Balanced

  • novel rearrangement containing the net normal amont of genomic material
  • normal phenotype
  • reproductive risk

Unbalanced

  • rearrangement associated with extra and/or missing genetic material
  • high likelihood of phenotypic abnormality
42
Q

Of the unbalanced structural abnormalities, describe partial trisomy and partial monosomy

A

partial trisomy

  • a structural abnormality that results in 3 copies of a particular chromosome segment

partial monosomy

  • structural abnormality resulting in only one copy of a chromosome segment
  • high risk of abnormal phenotype
43
Q

Of the unbalanced structural abnormalities, describe de novo and familial characteristics

A

De novo

  • structural abnormalities that are “new” (present in offspring but not in either parent)

Familial

  • structural abnormalities that segregate through a pedigree in balanced form, occasionally giving rise to an unbalanced offspring
44
Q

Of the unbalanced structural abnormalities, describe constitutional and acquired characteristics

A

Constitutional

  • present in all cells of the body

Acquired

  • abnormality arising in somatic cell of a single tissue => typically in cancer lineages
  • (refers to abnormalites in malignant cells but note difference between mosaicism which is mixed pop. of nonmalignant cells)
45
Q

What are phenotypic consequences of unbalanced karyotypes?

A

in general autosomal imbalance causes

  • developmental delay (intellectual disability)
  • growth delay
  • facial dysmorphology and physical malformations
  • congenital organ malformations, such as heart defects
46
Q

What are phenotypic consequences of unbalanced karyotypes wrt mosaicism, sex chromosomes, lethality

A

presence of mosaicism (abnormal + abnormal cell lines) => generally less severe phenotype

imbalance involving sex chromosomes => generally less severe phenotype than autosomal imbalance

larger the imbalance, greater the risk of lethality (phenotypic consequences of monosomy>trisomy)

47
Q

Wrt breakage/exchange of translocations, describe reciprocal translocation

A
  • 2 break, reciprocal rearrangement
  • exchange of segments between 2 nonhomologous chromosomes
  • Random => breakpoints can be anywhere, in any 2 chromosomes
  • Balanced carrier => phenotypically normal, with reproductive risks
48
Q

Describe meiotic segregation of reciprocal translocations

A

most likely segregation pattern for the majority of translocations (alternate)

  • gamete receives the 2 normal chromosomes OR the 2 abnormal chromosomes
  • balanced
  • phenotypically normal offspring

Risk-associated segregation patterns (adjacent)

  • gamete receives one normal + one abnormal chromosome
  • unbalanced (partial monosomy/partial trisomy)
  • High risk of phenotypic abnormalities or SAb
49
Q

Of the reciprocal tranlocation carriers possible, what are the reproductive outcomes?

A
  1. chromosomally normal
  2. balanced carrier
  3. partial trisomy (2) and parial monosomy (15)
  4. partial monosomy (2) and partial trisomy (15)
50
Q

Describe the robertsonian translocations

A
  1. Long arm fusion of any 2 acrocentric chromosomes
  2. balanced carrier has chromosome number of 45
  3. acrocentric short arm material frequently is lost. it is redundant and its loss causes no phenotypic consequence
  • fusion chromosome has a single functional centromere
  • acrocentric chromosomes 13, 14, 15, 21, 22
51
Q

What are the balanced robertsonian carrier possible reproductive outcomes?

A
  1. normal
  2. balanced carrier
  3. trisomy 14
  4. monosomy 14
  5. monosomy 21
  6. trisomy 21
52
Q

Describe the reproductive risks and what type of chromosomes can occur with robertsonian translocations

A

Robertsonian chromosomes can involve any 2 acrocentric chromosomes

reproductive risks vary

likelihood of liveborn, unbalanced offspring can be predicted based on known features of autosomal aneuploidies

53
Q

What are other structural abnormalities?

A
  1. deletions (terminal, interstitial)
  2. duplications
  3. inversions (pericentric, paracentric)
  4. ring chromosomes
54
Q

2 breaks in the same chromosomal arm (same side as centromere) can result in what two options?

A

paracentric inversion

interstitial deletion

55
Q

2 breaks in the different chromosomal arm (different sides of centromere) can result in what two options?

A

pericentric inversion

ring chromosome

56
Q

Describe the structural abnormality of deletion (unbalanced) (3 types)

A
  • partial monosomy for deleted segment
  • interstitial deletion (2 breaks on 1 arm and loss of segment with rejoining of broken arms)
  • terminal deletion (single break and loss of broken terminal segement along with acquisition of new telomere)
57
Q

Describe the structural abnormality isochromosome (unbalanced)

A

centromere misdivision at metaphase/anaphase

abnormal chromosome consisting of 2 copies of 1 arm (no copy of other arm)

partial trisomy and partial monosomy

58
Q

What are clinically important examples of isochromosome structural abnormalites i(Xq)?

A

Turner syndrome [46,X,i(Xq)]

i(21q) in translocation down syndrome [46,XY,i(21)q]

same as robersonian homologous long arm fusion

59
Q

Describe duplication (unbalanced)

A
  • duplication of segment
  • multiple possible mechanisms
  • parital trisomy for duplicated segment

46,XX,dup(2q)

60
Q

Describe the structural abnormality of inversion (balanced) wrt to phenotype and risk

A

balanced (normal phenotype)

Reproductive risk occurs with meitic recombination w/in paired inversion loop may give rise to unbalanced gamete

61
Q

How do paracentric and pericentric relate to inversion (balanced)?

A

paracentric is 2 breaks in same arm

pericentric is a break in p arm + break in q arm

62
Q

Describe cancer cytogenetics wrt to type, location and associations

A

Acquired abnormalites restricted to malignant cells

Genes (especially proto-oncogenes) located at breakpoint junctions form chimeric fusion genes with novel expression properties

100s of specific rearrangements are known to be associated with specific malignancies

63
Q

t(9;22) is seen consistenly in CML (chronic myelogenous leukemia). Describe this fusion mechanism

A

fusion gene (bcr-abl) exhibits increased tyrosine kinase activity, predisposing to hemtopoietic malignancy

64
Q

What are the steps in gene fusion?

A
65
Q

Is genomic instability typical in malignancies? how?

A

yes

malignant tissues typically have numerous chromosome abnormalities

genomic instability spans the genome

66
Q

What are the clinical consequences of reciprocal translocations?

A
  • since each translocation is unique and difficult to predict
  • for many reciprocal translocations, unbalanced segregants are nonviable
  • risk of liveborn offspring with multiple anomalies may be significant, since small segmental aneuploidies are better tolerated than complete aneuploidies
67
Q

T/F balanced carriers of reciprocal translocations can produce normal offspring

A

true

68
Q

WRT reciprocal translocation, which 2 results are common and which 2 are rare and possibly lethal?

A

common=> normal, translocation carrier

Rare, possibly lethal => duplication-deletion for both

69
Q

From parents, which one is a balanced carrier of chromosome translocation abnormality, What are the possible results? What is the likelihood that normal offspring have affected offspring?

A
  1. affected(unbalanced/viable),
  2. balanced carrier,
  3. normal,
  4. miscarriage (unbalanced/nonviable)

The normal offspring have lost the gene to have the affected offspring so all will be normal

70
Q

What is the nature of reproductive risk for reciprocal translocations?

A
  • incidence of balanced translocation carriers 1/500-1000 (normal phenotype)
  • often familial

3 categories of gametes produced

  1. normal => normal phenotype
  2. balanced => normal phenotype
  3. abnormal/unbalanced => abnormal phenotype or miscarriage
71
Q

What are some of the clinical consequences of reciprocal translocations?

A
  • often difficult to predict, since each translocation is unique. Genetic counseling, prenatal Dx, and pregnancy surveillance should be available
  • for many translocations, unbalanced segregants are large then nonviable
  • risk of liveborn offspring with multiple anomalies may be significant, since smal segmental aneuploids are better tolerated than complete aneuploidies
72
Q

T/F 3-5% of couples with recurrent losses have a chromosome abnormality

A

true

73
Q

robertsonian translocation is a translocation class involving what?

A

translocation of 2 long arms of the acrocentric chromosomes

occurs on 13,14, 15, 21, 22

74
Q

In robertsonian translocation, what happens when the short arms are lost in the event?

A

there is no clinical significance

75
Q

Robertsonian translocations have what as the most likely outcome? How does this arise?

A

equal proportions normal karyotype and balanced carrier

45% each (normal or bal. carrier) from mother so a 10% chance of unbalanced offspring for translocation down syndrome

49% each (normal or bal. carrier) from father but only a 1% chance for an unbalanced offspring for translocation down syndrome

76
Q

Robertsonian translocations can involve any 2 acrocentric chromosomes. However, most are not viable. On which chromosome do these translocations produce viable offspring?

A

chromosome 13 or 21

77
Q

An increased number of miscarriages is seen in what type of translocations?

A

robertsonian translocations

78
Q

Describe the special case of homologous robertsonians (isochromosomes)

A

fusion chromosome that has 2 copies of the same acrocentric long arm

possibly caused by centromere misdivision or long arm fusion event

as with all robersonians, balanced carriers have a chromosome number of 45 [45,XX,rob(14q14q)]

balanced carriers have close to a 0% to have healthy offspring

translocation down syndrome [46,XY,i(21q)]

79
Q

Deletions and duplications are clinical implications of partial monosomy and partial trisomy. Describe these

A

phenotypic consequences are driven by the net imbalance of genomic material (deletion vs duplication and its size)

may arise de novo

may be an unbalanced segregant of a familial rearrangemet (reciprocal translocaiton or inversion)

Diagnois by convential karyotype, FISH, or array CGH

80
Q

List the indications for chromosome analysis

A
  • confirm recognizable syndrome
  • multiple congenital anomalies in fetus, stillborn, or infant
  • family members of known case
  • couples with multiple fetal losses or infertility
  • ambigous genitalia or delayed puberty
  • mental retardation with dysmorphia or anomalies
  • prenatal diagnosis for maternal age or other indications
81
Q
A

Genetics block 2 (6 decks)

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