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Flashcards in Prenatal genetic screening& diagnosis Deck (17)
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1

Outline chromosome abnormalities

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

2

List the whole chromosome abnormalities currently associated with a viability

-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

3

Explain why whole chromosome abnormalities occur

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

4

Explain how malsegregation produces whole chromosome aneuploidy

-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

5

How can we get a normal fetus despite whole chromosome aneuploidy

-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

6

What are chromosome translocations?

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

7

What are Robertsonian translocations?

-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

8

What are acrocentric chromsomes?

-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

9

What reproductive risks do balanced carriers of Robertsonian translocations have ?

-Recurrent miscarriages
-Patau syndrome
-Down syndrome
-Male infertility

10

What are reciprocal translocations?

-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

11

Outline the reproductive risk for reciprocal translocations

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

12

Explain deletions& duplications of DNA

-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

13

Outline monogenic disorders

-Inherited
-De novo
e.g CF, spinal muscular atrophy, Duchenne muscular dystrophy

14

How is prenatal testing carried out?

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

15

Outline quantitative fluorescence PCR ( QF-PCR)

-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

16

Outline array comparative genomic hybridization

-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

Outline the Rapid FISH test

-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