Genetics - E2 Flashcards
What is the difference between structural and acquired chromosomal abnormalities?
Structural: chromosome number stays at 46.
- translocation (t)
- deletion (del)
- duplication (dup)
- Inversion (inv)
- insertion (ins)
Constitutional: chromosome # changes from 46
- gain or loss of a chromosome
Which trisomies are compatible with life?
13, 18, 21
+X
+Y
What are the features of trisomy 18?
(Edwards syndrome) -Due to overspression of genes on chromosome 18
47 XX/XY +18
- Small size, small head circumference
- Congenital heart defects
- Overlapping fingers
- Rocker bottom feet
- Very poor prognosis, only 5% survive beyond 1 yr.
-long-term survivors –> severely delayed development
What are the features of trisomy 13?
(Patau Syndrome)
-scalp defects (cutis aplasia) microcephaly -micropthalmia -holoprosencephaly -cleft lip and palate
-long term survivors –> severe ID delay
What are the features of trisomy 21?
(Down syndrome)
- flat facial profile
- upslanted palpebral fissues
- anamalous auricles
- nuchal skin fold
- single palmar crease
- clinodactyly
- hypotonia
- hyperflexibility of joints
Associated
- Intellectual disabilities
- congenital heart disease (AV valve)
- gastrointestinal abnormalities
- atlantoaxial instability
- strabismus
- thyroid abnormalities
What are the features of Turner syndrome?
45X (50%, shown to be of maternal origin in 60-80% of cases, consistent with paternal meiotic error –> no sperm on x chromosome * can occur in M1/M2), 46X (abnormal X)
Features:
- lymphedema in infancy
- bicuspid aortic valve, coarctation of aorta
- short stature (adult height <150cm without GH)
- gonadal regression (streak ovaries)
- Low posterior hairline, webbed neck, widely spaced nipples
- abnormal arm carrying angle
-
What are the features of Klinefelter syndrome?
47XXY
- tall stature
- learning difference
- gynocomastia
- small testicles
- Infertility due to hypogonadism with oligospermia/azoospermia
What are the features of 47XXX, 47XYY?
47XXX - Speech delays, IQ 10-15 points below siblings, increased risk infertility, most offspring have normal chromosomes.
47XYY- IQ below siblings, impulsive w/ emotional immaturity, most offspring are chromosomal normal
What are the 3 steps of chromosome inactivation?
Counting, choice, cis inactivation
When both X chromosomes are normal, how is x-inact chosen?
Randomly
When abnormal X is present, how is x-inact chosen?
Abnormal X is inactivated preferentially (if contains XIST)
If there was a translocation between X and autosome, how is x-inact chosen?
Normal X is inactivated.
If there was an unbalanced X translocation, how is x-inact chosen?
Abnormal X inactivated.
What is the pseudoautosomal region of the X chromosome?
Region that pairs with Y chromosome in meiosis.
Escapes X inactivation.
heterodisomy
If the contributing parent provides one copy of each homologous chromosome (as a result of non-disjunction in meiosis I)
isodisomy
If the parent passed on two identical copies of the same chromosome (as a result of non-disjunction in meiosis II)
What is one mechanism of UPD occurrence?
Trisomic rescue after hetero/isodisomy
What are the features of micro deletion syndromes?
They are often result of submicroscopic deletion of more than 1 gene from the chromosome.
Multiple genes –> physically continguous (picket fence) o a chromosome
Phenotype correlates with specific genes lost (bigger deletions, more features)
Usually sporadic, but can be dominant.
Need FISH to diagnose the deletion
Examples of micro deletion syndromes
DiGeorge syndrome
William’s syndrome
Unbalanced translocations have combination of …
monosomy and trisomy
how can any balanced translocation lead to an unbalanced translocation in offspring
- Chromosomes have to pair to crossover and then separate to go to daughter cells.
- There is independent assortment of chromosomes, so there is no way to ensure that the normal chromosomes of someone with a balanced translocation go to the same daughter cell or that the two derivative chromosomes end up in the same cell.
Robertsonian translocations occurs between…
Acrocentic chrom (no short arm): 13, 14, 15, 21, 22
Robertsonian translocations are different from other chromosomes in what way?
Robertosonian translocations result in loss of non-critical genes in the short arm regions of the chromosomes involved.
What does “q10” mean in Robertsonian nomenclature?
The break is in the centromere and the long arm is present.
In Robertsonian translocations, the chromosome count is…
decreased to 45.
What are the two types of inversions and what to they entail?
Pericentric inversions: around the centromere (p and q breakpoints)
Paracentric inversions: outside centromere (breakpoints match)
When and where do acquired changes occur?
Not present at birth. Changes occur only in organ affected.
Patient’s phenotype (appearance) is unchanged by any cancer associated translocation.
Cancer is assoc with genetic change, often seen as change in karyotype.
What are some types of acquired changes?
Changes in copy number of virtually any chromosome, balanced translocations, unbalanced translocations, deletions/duplications
Describe clonal evolution and when it occurs
- The presence of additional karyotype changes is termed clonal evolution, which usually occurs when there is disease progression.
- As changes get more complex, unbalanced translocations (one part of the exchange missing) become more frequent.
Why do translocations recur in cancer?
- Breakpoints = locations of oncogenes
- Result in prod of abnormal protein that cannot be regulated/overproduction of a normal protein
Why do deletions happiness in cancer?
Bc of loss of genes controlling cell cycle
Loss of one copy of gene and possible inactivation of other copy removes cell cycle control point
Where are deletions usually located?
In coding DNA or regulation sequences
What are micro deletion syndrome?
A constellation of findings due to a specific deletion that encompasses several genes. (not visible in karyotype)
Describe null mutations
(loss of function)
50% of function is sufficient.
Carriers are healthy.
Exp. PKU
Describe haploinsufficiency
(AD)
- half of normal prod is insufficient for normal function. One abnormal allele=likely mild disease
- severe disease: inherited as AR condition = two abnormal alleles
- also called INCOMPLETE DOMINANCE
exp. Familial Hypercholesterolemia
Describe dominant negative mutations
(AD)
- mutant product is produced from one allele
- mutant protein interferes with function
- Exp. Marfan syndrome (defective fibrin interferes with elastin)
Describe gain of function mutations
Due to a very particular change in the gene
Causes new/gain of function of the protein product
Only ONE mutant gene is necessary (AD)
Exp. Achondroplasia
Karyotype
detects visible chromosome abnormalities (>3MB)
exp. deletions, duplications, translocations, inversions, insertions
FISH
known submicroscopic deletion and duplication syndromes (detects smaller than FISH)
Methylation-specific PCR
differentiates between segments of DNA that are methylated (turned off)
Used to detect if imprinted regions are present in their appropriations #
Allele-specific oligonucleotide testing
used to look for panel of common mutations in given gene or several genes
Exp. probes for detecting 23 most common CF mutants
STRPS
short tandem repeats polymorphisms
exp. crime scenes, paternity, twin testing
What are the objectives of population screening?
- pres-symptomatic detection
- reproductive decision making
- benefits should outweigh costs
- optimize sensitivity and specificity
- provides screening and not testing
SNP arrays
screen for genome wide variation
- may/may not change AA
- ask which SNP is present (expected to have 2 copies at each position).
- In addition to detecting dup/delet –> can detect regions of homozygosity
- can reveal loss of heterozygosity or identify UPD
- will only ID isodisomy (M2), not heterodisomy (M1)
- provides more info than CHG
CGH arrays
screen for genome wide variation
- measure change in gene regulation (control vs patient)
- looking for duplication/deletion
Arrays
screen for genome wide variation
