Imprinting Flashcards
Approximately _% of imprinted disorders are paternally imprinted
67%
Paternally imprinted allele def + example
expression comes from maternal allele
UBE3A, CDKN1C
maternal imprinted allele def + examples
expression is from paternal allele
SNRPN, IGF2
Clues that imprinting may be involved
Association of uniparental disomy with abnormal development
Association of consistent parental origin of pathogenic allele in inherited disorder
Russel Silverman Genetics
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
Russell Silverman features
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
Psychosocial aspects of RSS
Challenges of feeling and looking different
Pain, disability, and fatigue
Anticipated stigma
Building resilience and acceptance
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
Under expression of growth promoting genes & overexpression of growth limiting genes
Beckwith Wiedman chromosome
11
Beckwith Wiedman genes
CDKN1C, KCNQ1, IGF2, H19
Cardinal features of Beckwith Wiedman
Macroglossia
Omphalocele
Lateralized overgrowth
Multifocal and/bilateral Wilms tumor or nephroblastoma
Hyperinsulinism
Suggestive features of Beckwith wiedman
Large birth weight
Facial nevus simplex
Polyhydramnios and/or placentomegaly
Ear creases or pits
Mechanism for Beckwith wiedman
~50% loss of methylation of IC2 on the maternal chromosome
~20% UPD of 11p15.5
~20% unknown
In thinking about BWS, what is the underlying molecular mechanism?
Over expression of growth- promoting genes & under expression of growth limiting genes
Angelman chromosome, AND gene
Deletion in maternal Chromosome 15q11q13
UBE3A
Angolan clinical features
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
Behavior of Angelman
Frequent laughter/ smiling
Happy demeanor
excitability ; often with hand flapping
Short attention span
Prader willi chromosome
Deletion in paternal Chromosome 15q11q13
Prader willi is characterized by
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
Sexual development in PW
Few or no signs of puberty
Scant facial and pubic hair in males, small penis and testicles
Absent or scant menstrual periods in females
Underlying mechanism for PW
~70% of individuals with PWS have a deletion of chromosome 15 involving q11q13
mechanisms for alterations of imprinting
Deletions
Point mutations
Uniparental disomy
Epimutations
Reversal of imprint
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
UBE3A association
Associated with angelman
Only expressed from maternal allele
In PCR analysis if only maternal allele visible then
PWS
In PCR analysis if only paternal allele visible then
AS
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)?
Angelman syndrome
Method to determine deletion
Karyotype, FISH using SNRPN probe, microarray or MLPA
Method to detect UPD
Microsatellite, SNP array, MPLA analysis
Method to detect imprinting
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
Methylation sensitive MLPA cannot distinguish between
UPD and ID
Mechanisms of UPD
Trisomy rescue
monosomy rescue
gamete complementation
post zygotic somatic recombination
Of the mechanisms that can result in UPD, which is the least common?
Gamete complementation (it would require nondisjunction in both parents)
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?
Monosomy rescue
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?
Maternal meiosis I or II (we know dad gave 15 bc he is a carrie for the disorder)
Hypothesis linking ART and imprinting
Infertility per se predisposes to abnormal imprinting and or
Aspects of ART (for example ovarian hyperstimulation, in vitro embryo culture) predispose to abnormal imprinting
there is an established association between ART and _
BWS
