Imprinting, Cytogenetics, DS, PWS Flashcards
epigenetics
Mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence. Ex. DNA methylation and post-translational modifications of histones
Compact vs. open chromatin
Compact is repressed through methylation and repressive histone marks. Open has active histone marks and is not methylated
Methylation of CpG islands recruits which protein to silence gene expression?
MeCP2 recognized methylated cytosine. Recruits other proteins involved in repression
Genetic imprinting
Sex-dependent epigenetic modulation of regulatory regions. Males and females have different regions that are turned on or off via methylation of CpG islands. Less than 10% of genes
When is methylation established? Is it maintained or reversible?
Established in the gamete. Maintained in somatic cells but has to be reversible so it can be reset during gametogenesis.
Which enzyme propogates epigenetic marks in somatic cells?
Methytransferases. Methylate newly synthesized DNA strand
What are the DNA methylation imprinting patterns in germ line and somatic cells?
Epigenetic reprogramming occurs in germ cells. Somatic maintenance of imprinted regions occurs in somatic cells.
Why is erasure/resetting of methylation patterns of imprinted genes essential during gametogenesis?
Without erasure/resetting; half of primordial germ cells will have wrong imprinting. Ie; 1/2 of PGCs from each parent will have male imprinting and female imprinting.
What is deleted in Prader-Willi Syndrome?
Del(15q11-q13) on paternal chromosome. Only have maternal piece
What is deleted in Angelman syndrome?
Del(15q11-q13) on maternal chromosome. Only have paternal piece
What is the role of the imprinting center?
It �decides� which regions are expressed from maternal/paternal chromosome
What 3 mechanisms can cause PWS?
1) Deletion of paternal 15q11-13 (most common) 2) Maternal uniparental disomy (both chromosomes in this region came from mom) 3) Imprinting center is missing/mutated on paternal allele
What 4 mechanisms cause AS?
1) Deletion of maternal 15q11-13 (most common) 2) Paternal uniparental disomy 3) IC mutated/missing on maternal allele 4) Mutation of UBE3A gene on maternal allele (this is the only maternal gene that gets expressed in this region)
What leads to deletions in PWS/AS?
Presence of low copy repeats derived from gene HERC2. The repeats flanking 15q11-q13 may be involved in misalignment with leads to deletions during homolougs recombination.
What translocation is seen in chronic myeloid leukemia (CML)?
t(9;22)
What protein fusion product is commonly seen in CML?
BCR/ABL fusions
How can CML be treated?
Tyrosine kinase inhibitors aka Gleevec
How does Gleevec work?
In cells; phosphorylation is an “on” switch. In Ph-+ CML cells BCR-Abl is stuck in “on” and keeps phosphorylating groups. Gleevec binds to Abl or BCR-Abl and prevents phosphorylation. In turn prohibits cell proliferation.
What translocation is seen in acute pro-myeloid leukemia (APMO)?
t(15;17)
What protein fusion product is commonly seen in APMO?
PML-RARalpha
How can APMO be treated?
Retinoic acid aka Vitamin A (I think it has to be all-trans).
How does retinoic acid work?
It changes the conformation of the novel protein so that it allows for differentiation again.
What the common cytogenetic findings in childhood B-cell acute lymphoblastic leukemia (ALL)? How do cytogenetic findings influence patient prognosis?
High hyper-diploidy. High hyper-diploidy is good prognosis.
Name 5 types of FISH probes
Centromere; locus specific; dual fusion/fusion; break apart; whole chromosome paint
What is the name of the centromere FISH probe? What is it used for? What is an example?
Cen. Used for enumeration. Ex ALL panel; prenatal dx
What is the name of the locus specific FISH probe? What is it used for? What is an example?
LIS. Used for deletion/duplication. Ex p53 cancer
t is the name of the dual fusion/fusion FISH probe? What is it used for? What is an example?
DF;F. Used for translocation. Ex BCR-Abl; PML-RARalpha cancers
t is the name of the Break Apart FISH probe? What is it used for? What is an example?
BAP. Used for translocation rearragment. Ex MLL (cancer)
t is the name of the Whole Chromosome Paint FISH probe? What is it used for? What is an example?
WCP. Used for indentifying markers; translocations. Ex WCP 1-22; X; Y (all studies)
What are the 3 main causes of Down Syndrome?
Trisomy 21; Unbalanced translocation btwn 21 and another acrocentric chromosome (3-4%); Mosaic Tri 21 (1-2%)
What does 1st trimester screening for DS look at?
Ultrasound measurement of nuchal folds + Beta-hCG (human chorionic gonadotropin) + PAPP-A (pregnancy-associated plasma protein A). Detetion rate 82-87%
What does 2nd trimester screening for DS look at?
Quad screen. Beta-hCG (human chorionic gonadotropin); AFP (alpha-fetoprotein); unconjugated estriol; and inhibin level
If there is suspicion of DS based on 1st or second trimester screening; how can it be confirmed?
Chromosome analysis via amniocentesis or CVS (chorionic villus sampling)
What are common physical features of infants with DS?
Growth parameters are usually normal; midfacial hypoplasia; upslanting palpebral fissures; epicanthal folds; small ears; large-appearing tongue; low muscle tone; increased joint mobility; short fingers; transverse palmar crease; Vth finger incurving (clinodactyly); increased space between toes 1 and 2
What are common gastrointestinal structural anomalies seen in DS?
Esophageal atresia; duodenal atresia; hirschsprung’s. (Present in 10-15% of infants)
What functional GI issues do many children with DS have?
Feeding problems; constipation; GERD - all very common. Celiac Dz (recommended screen is TTG + IgA)
What % of DS Pts have cardiac issues? What is most common?
50%. All types of anomalies may be present butAtrioventricular Canal is common to DS
What type of ophthalmologic problems are common in DS?
Blocked tear ducts; myopia; lazy eye; Nystagmus; Cataracts
What ENT problems are common in DS pts?
Chronic ear infections; Deafness (sensorineural and conductive); chronic nasal congestion; enlarged tonsils and adenoids (obstructive apnea)
What Orthopedic problems are common in DS?
Hips; joint subluxation; atlantoaxial subluxation
What endococrine problems are common in DS?
Thyroid dz (most commonly hypothyroidism); Insulin Dependent Diabetes; Alopecia Areata; reduced fertility (but normal puberty)
What hematologic issues are common in DS?
Myeloproliferative disorder in the newborn; increased risk of leukemia (12-20x); Iron deficiency anemia
What developmental issues are common in DS?
Hypotonia delays gross motor development; Spectrum of intellectual disability (mild-moderate disabilities); speech problems (importance of sign language)
What psychiatric issues are seen in DS?
Depression; early Alzheimer�s; Autism (1/10)
What neurologic problems are common in DS?
Hypotonia (spectrum from mild-severe); Seizures (especially infantile spasms)
How do Prader-Willi newborns present?
Present with hypotonia; dysmorphic features (almond shaped eyes); undescended testicles; severe feeding problems; lighter pigmentation
What type of ophthalmologic problems are common in Prader-Willi?
Many; especially strabismus and nystagmus
What kind of testing can be done for PWS?
Can test for methylation of 15q11-13 OR if there is a deletion you would test with FISH or microarray
How do PWS toddlers/preschoolers present?
Feeding problems completely reverse. Can lead to obesity
What kind of orthopedic problems are common in PWS?
scoliosis
What kind of respiratory problems are common with PWS?
Obstructive sleep apnea may develop and is a contraindication to use of growth hormone**
What kind of developmental problems are common in PWS?
Mild-moderate cognitive disabilities; behavioral issues
What other disorders are associated with chromosome 15Q?
Marker Chromosomes -Inverted duplication; Interstitial duplications; Deletions (Angelman syndrome). Also linkage disequilibrium btwn Autism and GABA-alpha-b3 locus on 15q
What is the phenotype of Pts with IDIC 15 AND maternally derived interstitial 15q duplications?
Autism; NOT dysmorphic; seizures common; hypotonia common during infancy
What is the phenotype of Pts with Angelman Syndrome?
dysmorphic facial features; hypotonia in infancy progressing to spasticity; Intellectual Disability (ID); seizures; autism
