Clinical cytogenetics: genomic imprinting & uniparental disomy

Question 1

T/F genomic imprinting is a normal developmental process

Answer 1

true

disruption is an underlying mechanism of genetic disease

Question 2

Mendelian inheritance is a special case of genomic imprinting. Describe it

Answer 2

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

Question 3

What causes Prader willi syndrome? What is its phenotype in infancy and childhood?>

Answer 3

caused by del(15) (q11q13) in most cases

infancy

• hypotonia
• feeding difficulties
• hypogonadism

childhood

• uncontrollable appetite; obesity
• moderate mental retardation

Question 4

What causes Angelman syndrome? and what does it present as?

Answer 4

caused by del(15)(q11q13) in most cases

• spasticity and seizures
• severe mental retardation
• growth retardation

Question 5

What are the 4 epigenetic mechanisms?

Answer 5

1. DNA modifications that influence gene expression and are heritable but reversible
2. DNA methylation in the regulation of gene expression (specificity may be dynamic)
3. X inactivation (heritable from cell to cell but not from generation to the next)
4. Genomic imprinting (parent of origin effects transmitted through gametes)

Question 6

Define Imprinting

Answer 6

**an epigenetic process (heritable but reversible) **

DNA methylation is a common mechanism for epigenetic control of gene expression

Question 7

IGF-2 and KVLQT1 are examples of imprinted genes on chromosome 11. Describe how and where they are expressed

Answer 7

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

Question 8

SNRPN and UBE3A are examples of imprinted genes found on chromosome 15. Describe how they are expressed

Answer 8

• SNRPN is 15q12
• paternaly copy expressed
• UBE3A is on chromosome 15q12
• **maternal copy expressed in brain **
• biallelic expression elsewhere

Question 9

What is the imprinted gene cluster (ICR) at 15q11-q13 action?

Answer 9

ICR is involved in setting the imprint for genes shown during gametogenesis

Question 10

What are the 3 steps in the imprinting cycle?

Answer 10

1. imprint switch during gametogenesis
2. pattern maintained throughout development & in the somatic tissues of the adult
3. in gametes, the imprint is reset for the next generation

Question 11

T/F during gametogenesis of sperm or ovaryies, an old imprint must be erased before a new one can be laid down

Answer 11

true

Question 12

Describe how parent specific imprints are made in the zygote

Answer 12

1. somatic cell with parent-of-origin imprint
2. gametogenesis: imprint is removed and re-imprinted according to sex of parent
3. parent specific imprints in zygote

Question 13

What is important about normal segregation and switching of imprint?

Answer 13

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 **

Question 14

What is the role of imprinting in genetic disease?

Answer 14

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

Question 15

Deletion “hotspot” includes both PWS and AS critical regions. Who is most affected and what is the parent of origin effect?

Answer 15

• 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

Question 16

What is significant about common breakpoints?

Answer 16

unequal crossover between low copy repeats at BP1/BP2 and BP3 causing microdeletion

Question 17

What are the 3 primary causes of PWS or prader-willi syndrome?

Answer 17

no paternal contribution of 15q12 critical region (1 or 2 maternally derived copies)

1. 70% paternal deletion (microdeletion)
2. 28% maternal uniparental disomy
3. 2% mutation of the imprinting center

Question 18

What are the 5 primary causes of Angelman syndrome?

Answer 18

No functional maternal contribution of 15q12 critical region (1 or 2 paternally derived copies)

1. 70% maternal deletion (microdeletion)
2. >5% paternal uniparental disomy
3. <5% mutation of the imprinting center
4. 10% UBE3A point mutations (familial)
5. 10% unknown

Question 19

How is angelman syndrom inherited?

Answer 19

can be inherited as a single gene defect, in addition to the sporadic mechanisms it shares with PWS

Question 20

Define uniparental disomy

Answer 20

situation where an individual inherits both chromosomes of 1 homologous pair from single parent and no copy of that chromosome from the other parent

Question 21

Describe the genetic amount and frequency in uniparental disomy

Answer 21

individual has the correct amount of genetic material, but parental origin is aberrant

rare

Question 22

What causes UPD (uniparental disomy)?

Answer 22

1. 2 separate nondisjunction events in the gametogenesis and/or embyrogenesis of a single individual
2. trisomy rescue

Question 23

What is trisomy rescue?

Answer 23

trisomy caused by (maternal) meiotic nondisjunction followed by chromosome loss through mitotic nondisjunction

Question 24

What must occur to give rise to UPD?

Answer 24

two INDEPENDENT errors

Question 25

What are some diseases caused from genomic imprinting?

Answer 25

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

Question 26

What are the 2 diseases that have the same genotype of del(15)(q11q13)? What causes this?

Answer 26

Angelman syndrome

prader-willi syndrome

genomic imprinting

Question 27

Pronuclear transplant experiments proved what wrt genome?

Answer 27

mammals need both paternal and maternal contributions required for normal development

Question 28

In SNRPN, which allele is on or off?

Answer 28

paternal copy is on

Question 29

In UBE3A, which allele is on?

Answer 29

only maternal on in brain

both are on elsewhere

Question 30

What is the primary mechanism for genomic imprinting?

Answer 30

DNA methylation

Question 31

unequal crossing over between low copy repeats causes what? What is important of these?

Answer 31

microdeletions

if you look at many patients then the small variants will affect the phenotype

Question 32

What will give you UPD?

Answer 32

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