Prenatal genetic screening& diagnosis Flashcards
Outline chromosome abnormalities
- ) Aneuploidy:
- Too many/few chromosomes - ) Rearrangements:
- translocations: balanced/unbalanced
- inversions
- complex chromosome rearrangements (CCRs) - ) Deletions/duplications
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
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
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
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
What are chromosome translocations?
-Exchange of material between chromosomes
2 types…
1.) ROBERTSONIAN
2.) RECIPROCAL
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
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
What reproductive risks do balanced carriers of Robertsonian translocations have ?
- Recurrent miscarriages
- Patau syndrome
- Down syndrome
- Male infertility
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
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
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
Outline monogenic disorders
- Inherited
- De novo
e. g CF, spinal muscular atrophy, Duchenne muscular dystrophy
How is prenatal testing carried out?
- ) INVASIVE
- Chorionic villus sampling
- Amniotic fluid sampling
- Fetal blood sampling - ) NON-INVASIVE
- peripheral maternal blood sampling eg biochemical screening
- analysis of free fetal DNA in the maternal circulation
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
