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Study and Diagnosis of Disease > Lecture 18 - Epigenetics and Imprinting Disorders > Flashcards

Lecture 18 - Epigenetics and Imprinting Disorders Flashcards

1
Q

What is epigenetics

A

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

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2
Q

How does DNA methylation occur

A
  • 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
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3
Q

What is the location of methylation

A
  • intergenic regions
  • CpG islands
  • within genes at CpGs
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4
Q

What does methylation do

A

silences genes

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5
Q

What does aberrant DNA methylation lead to

A
  • cancer
  • neurological disorders
  • psychological disorders
  • developmental disorders
  • autoimmune disease
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6
Q

What are somatic changes

A

changes that occur outside of the germline

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7
Q

What are germline changes

A

changes in the gamete producers that are passed to offspring

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8
Q

What is genomic imprinting

A

a gene is expressed or silenced depends on who it’s from

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9
Q

How was genomic imprinting discovered

A

pathogenesis and androgens

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10
Q

What are molar pregnancies

A

hydatiform mole: type of gestational trophoblastic disease
complete moles: 46 XX or 46 XY all paternal
partial moles: triploid karyotype

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11
Q

Why does imprinting occur

A
  • 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
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12
Q

What are imprinting control regions

A

*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

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13
Q

How do labs investigate diagnosis of imprinting disorders

A
  • uniparental disomy testing
  • methylation sensitive multiplex ligation dependent probe amplification
  • chromosomal microarray
  • next generation sequencing
  • bisulfite sequencing, methylation arrays
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14
Q

What is beckwith-weidmann syndrome

A

abnormalities in IC1 or IC2 which turns off IGF2

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15
Q

What are the features of beckwith-wiedmann syndrome

A
  • 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
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16
Q

What are the molecular genetics of BWS

A
  • 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
17
Q

What are the features of silver-russell syndrome

A
  • 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)
18
Q

What are the molecular genetics of silver-russell syndrome

A
  • 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
19
Q

What is prader willi syndrome

A

a hyperphasic disorder that drives you to eat

20
Q

What are the features of prader willi syndrome

A
  • 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
21
Q

What are the molecular genetics of prader willi syndrome

A

*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

22
Q

What are the features of angelman syndrome

A
  • 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
23
Q

What are the molecular genetics of angelman syndrome

A

*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

24
Q

What is Kleefstra syndrome

A

pathogenic variations of deletions of EHMT1

25
Q

What is Rett syndrome

A

pathogenic variants in MECP2

Study and Diagnosis of Disease (18 decks)

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