Term
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Definition
1)Heritable changes that do not depend upon DNA sequence changes
2)Principally occurs as a result of change in methylation status of DNA and acetylation of histones |
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Term
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Definition
1)Epigenetics is the study of heritable changes, that do not depend upon DNA sequence changes, principally occurring as a result of changes in methylation and acetylation of DNA
2)45,X Turner Syndrome and mosaic variants of Turner Syndrome are the only viable states of monosomy, nonetheless few survive to full term gestation, but those that do are relatively mildly clinically affected.
3)One extra X chromosome has a relatively mild clinical presentation, but multiple Xs are usually associated with major clinical problems.
4)X-inactivation is an example of epigenetics
5)The purpose of X-inactivation is male:female dosage equivalence, controlled via an interplay between the X-inactivation Center (XIC), the X controlling element (Xce) and the XIST gene.
6)The XIST gene is unique in that expression only occurs from the inactive chromosome.
7)If the XIST gene is missing (because of a structurally abnormal X chromosome) then this X chromosome cannot be inactivated, hence two copies of the X-linked genes are expressed, compared to the usual one copy.
8)A number of X chromosome genes are not subject to X-inactivation. This provides one explanation of increasing clinical severity with increasing number of sex chromosomes.
9)Sexual development is initiated in the embryonic stage from an original “indifferent gonad”. Female development occurs in the absence of the male determining gene SRY, but SRY alone is insufficient since there are a cascade of other genes expressed for male sex development.
10)Transfer of the SRY gene to the X chromosome leads to XX males and XY females.
11)Errors in the sex determination mechanism may lead to aberrations in the gonads, ductal system and/or genitalia.
12)Intersex occurs as a result of mosaicism (two cell lines in one individual conception) or chimerism (two individuals conceptions fused together to form one individual)
13)Prader-Willi and Angelman Syndromes are different clinical conditions caused by different but contiguous genes on chromosome 15, the cause of both is very similar and utilize the same testing methods
14)Microdeletion are too small for cytogenetics, so FISH or aCGH are the usual approaches to diagnose PWS/AS.
15)aCGH has the advantage of also looking at the entire genome for microdeletion or microduplication in the event that the potential diagnosis is incorrect
16)PWD and AS are caused by a microdeletion within chromosome 15 or by UPD
17)Uniparental disomy (UPD) is the inheritance of two copies of the same chromosome (or segment) from one parent without contribution from the other parent.
18)UPD usually occurs as a result of “trisomy rescue” which implies post zygotic loss of one chromosome (to make the baby disomic) from an original trisomy conception
19)Identification of UPD requires tracking molecular genetic markers through a pedigree or, for some disorders, testing methylation status of the DNA using a particular molecular DNA testing approach
20)Genomic imprinting is the differential expression of chromosomes or genes depending upon the parent of origin.
21)Imprinting is normal, a type of gene regulation and expression.
22)Both UPD and genomic imprinting are examples of epigenetic mechanisms. |
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Term
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Definition
1)Clinically:
Short stature
Webbing of neck
Cystic hygroma prenatally
Delayed secondary sex characteristics
Gonadal dysgenesis
Increased carrying angle
30% heart defect
2)Karyotype 45,X
50% Turners monosomy X
50% mosaic with either numerical or structural anomalies of other sex chromosome
45,X / 46,XX
45,X / 46,X,del(X)(p12)
3)1/5,000 liveborn, >99% SAB
4)Usually loss of paternal sex chromosome *must have cross-over for meiosis to occur, X and Y do not cross-over at pseudo-autosomal site*
5)Monosomy possible for all chromosomes but only clinically relevant for 45,X
6)No maternal age effect |
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Term
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Definition
1)Clinically:
-Immature secondary sex characteristics
-Small testes, infertile
-Tall stature
-Gynecomastia (< 50%)
-No mental retardation
2)Karyotype 47,XXY
-Gain of X chromosome
-50% maternal
-50% paternal
3)1/1000 liveborn
4)No parental age effect |
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Term
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Definition
1)Increasing number of copies of sex chromosomes:
a)Female:
-48,XXXX
-49,XXXXX
b)Male:
-48,XXYY and 48,XXXY,
-49,XXXYY and 49,XXYYY
2)Clinically: increasing mental retardation and congenital anomalies with increased number of X chromosomes |
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Term
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Definition
| To determine number of barr bodies, you do this: Numbers of X chromosomes-1 |
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Term
1)What is different about the X chromosome compared to the autosomes?
2)Why does loss, or gain, of the X chromosome usually have relatively mild clinical consequences?
3)Why is gain of more than one X chromosome associated with increasing clinical problem? |
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Definition
1)The X (and Y) chromosome is implicated in sexual differentiation, autosomes are not.
2)Assuming you are a normal female, you will still have another copy of the X chromosome that can be expressed. If you gain an extra X chromosome, it will just get inactivated (80%).
3)You don't have inactivation of all but one X chromosome and thus you have increased expression of the X chromosome. |
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Term
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Definition
1)Xist Gene (expression only occurs on inactivated gene)
2)XIC = X-inactivation center
3)XCE = X-controlling element
80% inactivation
20% escape inactivation |
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Term
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Definition
Y Chromosome
1)SRY-make determining gene
SRY-->Testes (also activates MIF which inactivates Mullerian duct)-->Testosteorne-->Wolffian Duct-->internal gentalia (also goes to dihydoxytestosterone-->external gentalia)
2)Ovaries-->Oestradiol-->External female genatila, in the absence of testes, Mullerian duct forms internal female genitalia. |
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Term
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Definition
Males with XX (SRY) are very similar to Kleinfelter's syndrome.
Females with XY (no SR) are very similar to Turner's Syndrome. |
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Term
| Intersex (Hermaphrodite) (2) |
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Definition
Mosaic
and
Chimera
(You should know what they are) |
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Term
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Definition
1)Hypotonia
2)Obesity
3)Slow, moderated retarded
4)Small hands/feet
5)Hypogonadism in males
Mutation on paternal genes, two maternal copies. |
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Term
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Definition
1)Severe mental retardation
2)Ataxic gait
3)Inappropriate laughter – “happy puppet syndrome”
Mutation on maternal genes, two paternal copies. |
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Term
| Uniparental Disomy: an example of Epigenetics |
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Definition
1)UPD is defined as the inheritance of two copies of particular chromosome (or chromosome region) from one parent without representation from the other parent
2)UPD cannot be determined by cytogenetic or molecular cytogenetic techniques *would have to look at molecular bands*
3)One method is to track molecular genetic polymorphic markers within a family pedigree |
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Term
| Why should UPD cause clinical problems, i.e. why should it make any difference? |
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Definition
Imprinting, caused by methylation. So while you may have all the genetic material, you would have two genes with the same methylation pattern such that you would either not get expression from a PWS or a AS gene respectively but rather double expression from the expressed gene (look at the normal vs. PWS vs. AS slide if you don't know what I'm talking about).
1)Genomic imprinting is defined as the differential expression of a chromosome or chromosome region depending upon whether maternally or paternally inherited
2)Imprinting is a type of gene regulation occurring principally during embryonic development
3)Imprinting is:
Reversible/removable
Transmitted to embryo (heritable)
Affects gene activity
Normal phenomenon
4)Imprinting: two interdependent processes affecting DNA
Acetylation of histones
DNA modification by methylation
5)Not all chromosomes or genes are imprinted. |
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