Imprinting

Question 1

Approximately _% of imprinted disorders are paternally imprinted

Answer 1

67%

Question 2

Paternally imprinted allele def + example

Answer 2

expression comes from maternal allele
UBE3A, CDKN1C

Question 3

maternal imprinted allele def + examples

Answer 3

expression is from paternal allele
SNRPN, IGF2

Question 4

Clues that imprinting may be involved

Answer 4

Association of uniparental disomy with abnormal development
Association of consistent parental origin of pathogenic allele in inherited disorder

Question 5

Russel Silverman Genetics

Answer 5

Chromosome: 11p15.5, UPD or deletion in chromosome 7

HMGA2 gene on 12q14.3
Promotes IGF2 expression
Appears AD due to LOF variants

PLAG1 on 8q12.2
Promotes IGF2 expression
Appears to be AD cause of SRS due to LOF variants

Question 6

Russell Silverman features

Answer 6

Intra-uterine growth retardation
Proportionately short stature
Typical facial features
Triangular facies
Prominent forehead
Down turned mouth
Narrow chin
Limb-length asymmetry that may result from hemihypertrophy with diminished growth of the affected side
Developmental delay

Question 7

Psychosocial aspects of RSS

Answer 7

Challenges of feeling and looking different
Pain, disability, and fatigue
Anticipated stigma
Building resilience and acceptance

Question 8

Genetic testing only confirms 60% of cases with a clinical dx of RSS. If a new gene is discovered, what would you predict the mechanism to be

Answer 8

Under expression of growth promoting genes & overexpression of growth limiting genes

Question 9

Beckwith Wiedman chromosome

Answer 9

11

Question 10

Beckwith Wiedman genes

Answer 10

CDKN1C, KCNQ1, IGF2, H19

Question 11

Cardinal features of Beckwith Wiedman

Answer 11

Macroglossia
Omphalocele
Lateralized overgrowth
Multifocal and/bilateral Wilms tumor or nephroblastoma
Hyperinsulinism

Question 12

Suggestive features of Beckwith wiedman

Answer 12

Large birth weight
Facial nevus simplex
Polyhydramnios and/or placentomegaly
Ear creases or pits

Question 13

Mechanism for Beckwith wiedman

Answer 13

~50% loss of methylation of IC2 on the maternal chromosome
~20% UPD of 11p15.5
~20% unknown

Question 14

In thinking about BWS, what is the underlying molecular mechanism?

Answer 14

Over expression of growth- promoting genes & under expression of growth limiting genes

Question 15

Angelman chromosome, AND gene

Answer 15

Deletion in maternal Chromosome 15q11q13
UBE3A

Question 16

Angolan clinical features

Answer 16

Normal prenatal and birth history
Normal metabolic, hematologic, and chemical labs
Structurally normal brain
Developmental delay
Speech impairment
Movement or balance disorder; usually ataxia or gait
Slow growth in head circumference
Seizures

Question 17

Behavior of Angelman

Answer 17

Frequent laughter/ smiling
Happy demeanor
excitability ; often with hand flapping
Short attention span

Question 18

Prader willi chromosome

Answer 18

Deletion in paternal Chromosome 15q11q13

Question 19

Prader willi is characterized by

Answer 19

Severe hypotonia
Feeding difficulties in early infancy; followed by excessive eating and gradual development of morbid obesity
Delayed motor milestones and language development, cognitive impairment
Hypogonadism

Question 20

Sexual development in PW

Answer 20

Few or no signs of puberty
Scant facial and pubic hair in males, small penis and testicles
Absent or scant menstrual periods in females

Question 21

Underlying mechanism for PW

Answer 21

~70% of individuals with PWS have a deletion of chromosome 15 involving q11q13

Question 22

mechanisms for alterations of imprinting

Answer 22

Deletions
Point mutations
Uniparental disomy
Epimutations

Question 23

Reversal of imprint

Answer 23

During gametogenesis, we must erase the imprints that we inherited from our parents and reestablish them based upon our own sex
In essence, we must reimprint the chromosome we inherit from our parent of the opposite sex

Question 24

UBE3A association

Answer 24

Associated with angelman
Only expressed from maternal allele

Question 25

In PCR analysis if only maternal allele visible then

Answer 25

PWS

Question 26

In PCR analysis if only paternal allele visible then

Answer 26

AS

Question 27

If a women with PW syndrome due to a de novo paternal deletion transmits this chromosome 15 to her child, what will the phenotype be (assume normal gamete from partner)?

Answer 27

Angelman syndrome

Question 28

Method to determine deletion

Answer 28

Karyotype, FISH using SNRPN probe, microarray or MLPA

Question 29

Method to detect UPD

Answer 29

Microsatellite, SNP array, MPLA analysis

Question 30

Method to detect imprinting

Answer 30

Presumed in patients with an abnormality in parent- specific methylation imprint without evidence of deletion or UPD
Microdeletions detected by real time PCR or MLPA

Question 31

Methylation sensitive MLPA cannot distinguish between

Answer 31

UPD and ID

Question 32

Mechanisms of UPD

Answer 32

Trisomy rescue
monosomy rescue
gamete complementation
post zygotic somatic recombination

Question 33

Of the mechanisms that can result in UPD, which is the least common?

Answer 33

Gamete complementation (it would require nondisjunction in both parents)

Question 34

A boy is homozygous for a very rare mutation for which only his father is a carrier. A 1 million SNP chip shows the child is homozygous for all SNPs on the chromosome of interest, supporting complete isodisomy. What is the most likely mechanism?

Answer 34

Monosomy rescue

Question 35

A boy is homozygous for a very rare mutation for which only his father is a carrier. A 1 million SNP chip shows the child is homozygous for all SNPs on the chromosome of interest, supporting complete isodisomy. Nondisjunction occurred during?

Answer 35

Maternal meiosis I or II (we know dad gave 15 bc he is a carrie for the disorder)

Question 36

Hypothesis linking ART and imprinting

Answer 36

Infertility per se predisposes to abnormal imprinting and or
Aspects of ART (for example ovarian hyperstimulation, in vitro embryo culture) predispose to abnormal imprinting

Question 37

there is an established association between ART and _

Answer 37

BWS