Prenatal genetic screening& diagnosis Flashcards

1
Q

Outline chromosome abnormalities

A
  1. ) Aneuploidy:
    - Too many/few chromosomes
  2. ) Rearrangements:
    - translocations: balanced/unbalanced
    - inversions
    - complex chromosome rearrangements (CCRs)
  3. ) Deletions/duplications
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2
Q

List the whole chromosome abnormalities currently associated with a viability

A

-Trisomy 21= downsyndrome
-Trisomy 13=Patau’s
-Trisomy 18=Edward’s
X & Y associated with various viabilities…
- 45,X= Turner syndrome
-47, XXY= Klinefelter syndrome

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3
Q

Explain why whole chromosome abnormalities occur

A

Arise due to malsegregation, either:

  • In the gonad during meiosis—> abnormal gametes
  • During mitosis in the germline—> mosaicism in the gonad (mixture of normal& abnormal gametes)
  • During mitosis in the early embryo —-> mosaicism in the embryo
  • Any whole chromosome aneuploidy is generally associated with raised maternal age
  • Trisomy 21- 75% arise during female meiosis
  • Trisomy 18- 90% arise during female meiosis
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4
Q

Explain how malsegregation produces whole chromosome aneuploidy

A
  • MEIOTIC error during gametogenesis will result in abnormal gametes arising from that meiotic division
  • MITOTIC error will result in gonadal mosaicism in the germline; in the embryo this will result in a mosaic embryo. The abnormal cell lines may be extraembryonic or both dependent on where and when they rise
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5
Q

How can we get a normal fetus despite whole chromosome aneuploidy

A
  • If the aneuploidy affects the extraembryonic cells we can get a ‘normal’ fetus supported by an abnormal placenta
  • e.g if the trisomy 21 cell passes into the amnion or the placenta, not the embryo proper. We can still get a normal pregnancy if the baby itself is composed of normal cells
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6
Q

What are chromosome translocations?

A

-Exchange of material between chromosomes
2 types…
1.) ROBERTSONIAN
2.) RECIPROCAL

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7
Q

What are Robertsonian translocations?

A
  • Only involve the acrocentric chromosomes (13,14,15,21,22)
  • Result from the fusion of two acrocentric chromosomes
  • Don’t result in imbalance when lost because all these different chromosomes make up for that by having the same genes
  • Balaced carriers are phenotypically normal e.g 45,XX, der (13;14) (q10;q10)
    e. g most common:
  • der(13,14) (q10;q10) ; you have one normal chromsome 13 and 14 but the other 2 chromosomes have a break at the centromere regions. The p arms have been lost without any effect on the phenotype and the 2 long arms have been joined in a head-to-head fashion, which produces a robertsonian translocation chromosome
  • Balanced carriers have reproductive risks
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8
Q

What are acrocentric chromsomes?

A
  • Chromosomes 13,14,15,21,22
  • Have very short p arms; unlike normal chromosomes which have a long p arm,centrosome & long q arm
  • only encode rRNA
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9
Q

What reproductive risks do balanced carriers of Robertsonian translocations have ?

A
  • Recurrent miscarriages
  • Patau syndrome
  • Down syndrome
  • Male infertility
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10
Q

What are reciprocal translocations?

A
  • Exchange of material between 2 non-homologous chromosomes
  • Prevalence of 1 in 500
  • Balanced carriers are generally phenotypically normal
  • If we diagnose a de novo balanced reciprocal translocation we give ~ 5% risk of developmental delay as there is no family history
  • alternate segregation results in normal and balance products
  • adjacent segregation results in unbalanced products
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11
Q

Outline the reproductive risk for reciprocal translocations

A

Unbalanced products result in:

  • miscarriage (large segments)
  • Dysmorphic delayed child (small segments)
  • The risk that a couple will produce a live born child with chromosome imbalance due to a balanced reciprocal translocation carried by one parent may vary from <1% to ~ 40% depending on the size of the imbalanced regions& their genetic content
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12
Q

Explain deletions& duplications of DNA

A
  • Regions of DNA that are deleted/ duplicated
  • may result from recombination during meiosis or misalignment and crossover between homologues during mitosis
  • These imbalances may be recurrent, well characterused with specific & associated with specific syndromes e.g prader will syndrome and angelman syndrome
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13
Q

Outline monogenic disorders

A
  • Inherited
  • De novo
    e. g CF, spinal muscular atrophy, Duchenne muscular dystrophy
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14
Q

How is prenatal testing carried out?

A
  1. ) INVASIVE
    - Chorionic villus sampling
    - Amniotic fluid sampling
    - Fetal blood sampling
  2. ) NON-INVASIVE
    - peripheral maternal blood sampling eg biochemical screening
    - analysis of free fetal DNA in the maternal circulation
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15
Q

Outline quantitative fluorescence PCR ( QF-PCR)

A
  • Microsatellites markers used to identify and count chromosomes 13,18,21 & X/Y
  • Microsatellites= repetitive DNA sequences made up of repeat units 2-10bp in size
  • Located throughout the genome
  • Repeat sizes vary in human population
  • A method of rapid prenatal diagnosis
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16
Q

Outline array comparative genomic hybridization

A
  • Array CGH
  • Prenatal referrals with ultrasound abnormality are tested first by QF-PCR for trisomy 13,18 or 21
  • If this test is normal they are tested for chromosome imbalance across the whole genome using array CGH
  • Array CGH compares two complete genomes ( eg a sample and a normal control), detects differences in copy number across the entire genome with a sensitivity of approx, 120kb
  • Reporting time 10days
17
Q

Outline the Rapid FISH test

A

-For carries of balanced chromosome rearrangements
Couples where one partner is a known carrier of a balanced chromosome rearrangement are tested for:
-sporadic primary trisomy of chromosome 13,18 &21 by QF-PCR
-an unbalanced product of their chromosome rearrangement using rapid interphase FISH. The test is designed specifically for their unique chromosome rearrangement and a result is available in 24hours