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35 Cards in this Set
- Front
- Back
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What is mosaicism
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the presence of two or more genetically distinct cell populations in a single individual
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Types of mosaicisms
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Chromosomal
- generalized - tissue specific or Single gene |
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What is generalized mosaicism
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occurs in postzygotic divisions (may begin as a normal or abnormal karyotype if is chormosomal
- X-inactivation - mosaic down syndrome |
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What is X inactivation
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- soon after fertilization, somewhere bw 8 and 32 cell there is an irrevical decision so that in the indiv with 2 X chromosomes, one of the Xs shuts down for dosage compensation
- all the descendant of that cell will now have the same X chr shut down - mosicism is then represented in all tissues - may express recessive condition - 50/50 shut down of mat or pat X - ex calico cat |
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Mosaic down syndrome
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- conceptus could begin as a trisomy, then lose one 21 chromosome in a cell in the first several division (meiotic event)
- or could begin as normal conceptus but have nondysjunction during a subsequent mitotic division |
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How common is mosaic down syndrome in those kids with down syndrome?
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2%
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What is tissue specific mosaicism?
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- one particular area, tissue or organ has confined mosaicism
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3 types of tissue specific mosaicism
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- somatic
- germline (subtype of somatic) - confined placental mosaicism (CPM) |
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germline mosaicism
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a type of tissue specific (somatic) mosaisim
- ex osteogenesis imperfecta (almost always lethal) |
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If a germline mosaicism leads to baby born with osteogenesis imperfecta, what can you tell the mom about the likelihood of this recurring?
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observed recurrence is 6%
- more than baseline population risk for mutation (<1%) ( if it have been a recessive trait, the recurrence would be 25%) |
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What is confined placental mosaicism
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- occurs at or after the third post-zygotic division (after conception)
- more likely to be seen in the placenta; with no mosaisism at the level of the embryo - can arise from normal diploid or abnormal zygote |
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In development of placenta, blastocyst wall, inner cell mall give rise to?
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- blastocyst wall give rise to chorion
- inner cell mass give rise to: >the embryo (three cells only), >yolk sac, >allantois and >parts of amnion |
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How common is confined placental mosaicism in cases of mosaicism?
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2%
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What are some symptoms of CPM?
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- normal
- intrauterine growth retardation - occasional overgrowth - fetal death |
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Describe trisomic rescue
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- conception begins as a trisomy
- in some cells the extra chromosome gets lost - the 3 cells that form the fetus carry on with the right # of chromosomes |
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Why would there be poor fetal outcome in CPM?
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- suboptimal placental function
- particular chromosome involved matters - proportion of normal:abnomal cells - ofter normal cells have better growth and tend to outgrow the abnormal cell - |
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What % of CPM preg have prenatal or perinatal complications?
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16-21%
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What is the most common aneuploidy for conception?
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trisomy 16
- BUT not seen amoung live born fetuses (letal in a non-mosaic state) |
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What is uniparental disomy ?
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inherting all or part of a pair of chromosomes from one parent
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3 causes of UPD?
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- trisomic rescue
- monosomic rescue (goes back to 46 chr) - gametic complementation |
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UPD trisomic rescue
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- start out with trisomic conceptus
- then have post-zygotic loss of the extra chromosome - if corrected in embyroblast lineage (3 cells), you can have a euploid fetus with trisomic placenta - depends which chr gets lost during time of correction - may end up with one mat and one pat chr OR 2 from one parent (UPD) |
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What is genetic imprinting important in relation to UPD?
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- severity of symptoms will depend on how much imprinting is involved
- some genes are only active if they pass through the mother/father |
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Possible outcomes of trisomic rescue?
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- 1/3 : one pat on mat (bi-parental inheritance)
- 2/3 : 2 pat or mat (UPD) |
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Chr 15 and trisomic rescue
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- it really matters which chormosome is rescued for chr 15 because it has blocks where genes are either maternally or paternally imprinted
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Where would nondysjunction need to occur for fetus to end up with one homolgue of each? What is this called?
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meiosis 1 ( chr dont separate and therefore what goes to cell is both chromosomes and so at time of meiosis 2, you will have both mat/pat present)
= heterodysomy ( most common) |
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Where would the nondysjuction need to occur to end up with two homologues from one parent? What is this called?
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- Meiosis 2
- called isodisomy - chromatids (two copies of original chromosome) don't separate properly |
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If a CF gene is present on the isodisomic chromatid, will the child have CF?
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Yes. Isodisomy can uncover autosomal recessive disorders where the mutatins only came from one parent.
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Gametic complementation
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UPD - ex maternal nondysjuction + paternal nullisomy
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Clinical features of CPM and UPD
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- not yet well defined
- often difficult to differentiate the effects of CPM (ex trisomy 16) from the effects of UPD16 - IUGR displayed in both |
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Clinical feature of UPD
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- recessive disorder
- effects ay depend on the presence of imprinted genes - |
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What is imprinting?
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differential allelic expression depending on parent of origin
- need complete maternal and paternal sets of chromosomes from fetal development in mice - triploid gynogenic embryos - small placental tissue - triploid androgenic embryos - large placental with little or no embryo |
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What is prader-willi syndrom?
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15q11-13
- either paternal chr deleted or maternal UPD - presentation: massively obese - when born are skinny and hypotonic, but around at year they have a huge increase in appetite --> morbid obesity |
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What is angelman syndrome
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15q11-13
maternal chromosome deleted or paternal UPD - aka happy puppet - skinny appearance - do not thrive, many can't walk, minimal development |
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Somatic gene mosaicism
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- autosomal dominant
- individual is heterozygous for the mutation - cause cyst to develop in kidneys - individual is heterozygous but homozygous in terms of cysts - cysts cell are clonal ( from one cell or event) - mosaic for cells with only germline mutation and cells with both that and inactivation mutation - commonest genetic cause for chronic renal failure - another example is hereditary breast cancer (2 hit theory) |
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What to do with CVS result?
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- offer amniocentesis
- detailed US - may want to do UPD studies, depending on chr involved (eg chr 15) - careful follow up of preg |
