Lecture 18 - Epigenetics and Imprinting Disorders Flashcards
What is epigenetics
both heritable changes in gene activity and expression (in the
progeny of cells or of individuals) and also stable, long-term
alterations in the transcriptional potential of a cell that are not
necessarily heritable
How does DNA methylation occur
- DNMTs catalyze the transfer of a methyl group from S-adenyl methionine to the 5th carbon of cytosine to form 5-methylcytosine
- DNMT3a and DNMT3b establish new methylation patterns on unmodified DNA
- DNMT1 functions during replication to copy the DNA methylation pattern
What is the location of methylation
- intergenic regions
- CpG islands
- within genes at CpGs
What does methylation do
silences genes
What does aberrant DNA methylation lead to
- cancer
- neurological disorders
- psychological disorders
- developmental disorders
- autoimmune disease
What are somatic changes
changes that occur outside of the germline
What are germline changes
changes in the gamete producers that are passed to offspring
What is genomic imprinting
a gene is expressed or silenced depends on who it’s from
How was genomic imprinting discovered
pathogenesis and androgens
What are molar pregnancies
hydatiform mole: type of gestational trophoblastic disease
complete moles: 46 XX or 46 XY all paternal
partial moles: triploid karyotype
Why does imprinting occur
- Regulation of maternal offspring interactions
- Maternal and paternal genes have conflicting interests
- Viviparous polyandrous species – paternal genes benefit from
maximizing resources - Maternal genes benefit from promoting equal growth amongst all
embryos
What are imprinting control regions
*Imprinted genes are clustered in groups at imprinted loci
* Methylation is key for regulating these genes
*Gene expression is controlled by imprinting control regions (ICRs) that
are differentially methylated
*Genes that are silenced are said to be “imprinted” in these regions
*Differential expression of genes either from the maternal or paternal
allele
* Loss of normal imprinting can occur by several mechanisms
* Methylation patterns for the ICRs are established during development
of the gametes
How do labs investigate diagnosis of imprinting disorders
- uniparental disomy testing
- methylation sensitive multiplex ligation dependent probe amplification
- chromosomal microarray
- next generation sequencing
- bisulfite sequencing, methylation arrays
What is beckwith-weidmann syndrome
abnormalities in IC1 or IC2 which turns off IGF2
What are the features of beckwith-wiedmann syndrome
- Macrosomia (large size)
- Neonatal hypoglycemia (low blood sugar in first few weeks of life)
- Hemihyperplasia (one side of the body larger than the other)
- Macroglossia (large tongue)
- Omphalocele
- Ear creases/pits
- Kidney anomalies
- Childhood cancers – Wilm’s tumour (kidney tumour), hepatoblastoma (liver
tumour), screening in childhood for cancers - we screen the children for these
until age 8
What are the molecular genetics of BWS
- Loss of methylation at imprinting control centre 2 (IC2)(maternal) in
50% (epimutation)
*Gain of methylation at IC1 (maternal) in 5% (epimutation) - Paternal Uniparental Disomy (UPD) in 20%
- CDKN1C Pathogenic Variants in 5% without a family history of BWS
and 40% who have a family history of BWS - Cytogenetic inversion or translocation of 11p15.5 <1%
- Microdeletions, microduplications in 9%
- Recurrence risks depend upon molecular diagnosis
What are the features of silver-russell syndrome
- Asymmetric gestational growth restriction (relatively large head, small body)
- Post-natal growth failure
- Asymmetry, limb length discrepancy
- Prominent forehead
- Triangular face
- 5
th finger clinodactyly (curved inward) - Feeding difficulties
- Café-au-lait macules (birthmarks)
What are the molecular genetics of silver-russell syndrome
- 11p15.5 ICR1 hypomethylation (paternal)
- Copy number variants (microdeletions, microduplications)
chromosome 7 and 11p15.5 - Somatic mosaicism for maternal UPD11
- Maternal UPD7
- Mosaic trisomy 7
- Pathogenic variants in CDKN1C, IGF2, PLAG1, HMGA2
What is prader willi syndrome
a hyperphasic disorder that drives you to eat
What are the features of prader willi syndrome
- Severe hypotonia (low muscle tone, floppy baby) and feeding difficulties in
early infancy - Excess eating and development of morbid obesity in childhood
- Developmental delay, cognitive impairment
- Behavioural problems (skin picking, anxiety, obsessive compulsive,
manipulative behaviour, temper tantrums, compulsivity) - Infertility, incomplete pubertal development
- Short stature
- Characteristic facial features
- Treatment with growth hormone is standard of care to prevent some of the
complications of obesity
What are the molecular genetics of prader willi syndrome
*Interstitial 5 to 6 Mb deletion of 15q11.2-q13 (paternal)
*Unbalanced chromosome rearrangement
* Maternal UPD chromosome 15
*Imprinting defect with deletion in the Imprinting Centre (IC)
* Epimutation without deletion in the IC
What are the features of angelman syndrome
- Severe developmental delay, intellectual disability, speech impairment
- Gait ataxia (unstead wide based gait), tremulousness of the limbs
- Unique behaviour (frequent laughing, smiling, excitability)
- Seizures
- Microcephaly (small head size) with onset after birth
What are the molecular genetics of angelman syndrome
*Interstitial 5 to 6 Mb deletion of 15q11.2-q13 (maternal)
* Paternal UPD chromosome 15
*Imprinting defect with deletion in the Imprinting Centre (IC)
* Epimutation without deletion in the IC
* Pathogenic variants in the UBE3A gene
* Chromosome rearrangement involving 15
What is Kleefstra syndrome
pathogenic variations of deletions of EHMT1
What is Rett syndrome
pathogenic variants in MECP2
