Clinical cytogenetics: genomic imprinting & uniparental disomy Flashcards
T/F genomic imprinting is a normal developmental process
true
disruption is an underlying mechanism of genetic disease
Mendelian inheritance is a special case of genomic imprinting. Describe it
each parent’s genetic contribution is equivalent
biallelic expression =>copies from each parent are expected to express equally in the child
genomic imprinting is an exception to this expectation
What causes Prader willi syndrome? What is its phenotype in infancy and childhood?>
caused by del(15) (q11q13) in most cases
infancy
- hypotonia
- feeding difficulties
- hypogonadism
childhood
- uncontrollable appetite; obesity
- moderate mental retardation
What causes Angelman syndrome? and what does it present as?
caused by del(15)(q11q13) in most cases
- spasticity and seizures
- severe mental retardation
- growth retardation
What are the 4 epigenetic mechanisms?
- DNA modifications that influence gene expression and are heritable but reversible
- DNA methylation in the regulation of gene expression (specificity may be dynamic)
- X inactivation (heritable from cell to cell but not from generation to the next)
- Genomic imprinting (parent of origin effects transmitted through gametes)
Define Imprinting
**an epigenetic process (heritable but reversible) **
DNA methylation is a common mechanism for epigenetic control of gene expression
IGF-2 and KVLQT1 are examples of imprinted genes on chromosome 11. Describe how and where they are expressed
IGF-2 is on chromosome 11p15 and is paternally copy expressed
Biallelic expression in some tissues
KVLQT1 is on chromosome 11p15 and is maternally copy expressed
Biallelic expression in heart
SNRPN and UBE3A are examples of imprinted genes found on chromosome 15. Describe how they are expressed
- SNRPN is 15q12
- paternaly copy expressed
- UBE3A is on chromosome 15q12
- **maternal copy expressed in brain **
- biallelic expression elsewhere
What is the imprinted gene cluster (ICR) at 15q11-q13 action?
ICR is involved in setting the imprint for genes shown during gametogenesis
What are the 3 steps in the imprinting cycle?
- imprint switch during gametogenesis
- pattern maintained throughout development & in the somatic tissues of the adult
- in gametes, the imprint is reset for the next generation
T/F during gametogenesis of sperm or ovaryies, an old imprint must be erased before a new one can be laid down
true
Describe how parent specific imprints are made in the zygote
- somatic cell with parent-of-origin imprint
- gametogenesis: imprint is removed and re-imprinted according to sex of parent
- parent specific imprints in zygote
What is important about normal segregation and switching of imprint?
under normal mendelian segregaton and polymorphism lies w/in an imprinted gene
**the maternally derived copy is silenced while only the paternally-derived allele is expressed in each individual **
What is the role of imprinting in genetic disease?
parent-of-origin effect on disease:
- When only one allele is normally active, disease presents when that allele is disabled by any one of multiple possible mechanisms
Deletion “hotspot” includes both PWS and AS critical regions. Who is most affected and what is the parent of origin effect?
- most affected individuals have a large delection with relative uniform breakpoints: 46,XX,del(15)(q11q13)
Parent of origin effect
- paternal deletion => PWS
- maternal deletion => AS
What is significant about common breakpoints?
unequal crossover between low copy repeats at BP1/BP2 and BP3 causing microdeletion
What are the 3 primary causes of PWS or prader-willi syndrome?
no paternal contribution of 15q12 critical region (1 or 2 maternally derived copies)
- 70% paternal deletion (microdeletion)
- 28% maternal uniparental disomy
- 2% mutation of the imprinting center
What are the 5 primary causes of Angelman syndrome?
No functional maternal contribution of 15q12 critical region (1 or 2 paternally derived copies)
- 70% maternal deletion (microdeletion)
- >5% paternal uniparental disomy
- <5% mutation of the imprinting center
- 10% UBE3A point mutations (familial)
- 10% unknown
How is angelman syndrom inherited?
can be inherited as a single gene defect, in addition to the sporadic mechanisms it shares with PWS
Define uniparental disomy
situation where an individual inherits both chromosomes of 1 homologous pair from single parent and no copy of that chromosome from the other parent
Describe the genetic amount and frequency in uniparental disomy
individual has the correct amount of genetic material, but parental origin is aberrant
rare
What causes UPD (uniparental disomy)?
- 2 separate nondisjunction events in the gametogenesis and/or embyrogenesis of a single individual
- trisomy rescue
What is trisomy rescue?
trisomy caused by (maternal) meiotic nondisjunction followed by chromosome loss through mitotic nondisjunction
What must occur to give rise to UPD?
two INDEPENDENT errors
What are some diseases caused from genomic imprinting?
chromosome 11p15 -Beckwith-Wiedemann syndrome (overgrowth syndrome; embryonal tumors, including Wilm’s tumor)
chromosomes 7 or 11 - Russell-silver syndrome (growth disorder)
LOI (loss of imprinting) in tumors
What are the 2 diseases that have the same genotype of del(15)(q11q13)? What causes this?
Angelman syndrome
prader-willi syndrome
genomic imprinting
Pronuclear transplant experiments proved what wrt genome?
mammals need both paternal and maternal contributions required for normal development
In SNRPN, which allele is on or off?
paternal copy is on
In UBE3A, which allele is on?
only maternal on in brain
both are on elsewhere
What is the primary mechanism for genomic imprinting?
DNA methylation
unequal crossing over between low copy repeats causes what? What is important of these?
microdeletions
if you look at many patients then the small variants will affect the phenotype
What will give you UPD?
trisomy rescue can form a normal karyotype
1/3 of sperm can be joined to give prader willi syndrome
if 1/3 comes from mother then everything will be good for the child
