Cytogenetics and Chromosomal Basis of Disease Flashcards
what is cytogenetics
study of chromosomes and their abnormalities
% occurrence of chromosomal abnormalities?
1/150 live births
50% of 1st trimester and 20% of 2nd semester spontaneous abortions
how to do karyotype?
- collect living tissue (blood)
- culture for 48-72 hours
- induce arrest at metaphase because the chromosomes are most condensed
- fix and stain
- photograph
what is metacentric
the chromosomal arms (p and q) are roughly the same length
what is submetacentraic
chromosome arms (centromere) is off center (skewed toward one end)
what is acrocentric
centromere is near end of chromosome
which arm is p arm
short arm (petite)
which arm is q arm
long arm
staining techniques for chromosome staining
- G banding
- Q banding
- R banding
how to G band
Giemsa stain, bands are determined on base composition of G-C base
how to Q band
quinacrine mustard, seen via fluoroscence microscopy, correspond to G banding
how to R band
chromosomes are heat treated before staining, the bands are reverse from G and Q banding
why are different techniques used for chromosome staining
to see different views of chromosomes
what exactly is stained in karyogram/karyotypes
T lymphocytes in metaphase are fixed and stained
how are karyotypes looked at
fluorescence in situ hybridization (FISH), where DNA probes/complementary DNA sequences labeled with fluorescent tags. the probe binds the sequence looking for on chromosome.
what is best seen in FISH?
chromosomal rearrangements, copy number, and how many alleles of that particular gene there are in a cell (deletions, duplications), fusions
what is spectral karyotype
expansion of FISH where each chromosome is labeled with a different colored probe (greater resolution and can see more details)
benefits of spectral karyotype
can detect small chromosome rearrangements
what is comparative genomic hybridization and array CG?
- DNA probes are bound to the array that represent portions of the genome (loci and telomeres)
- microarray is exposed to labeled patient and control DNA
- sample is analyzed for differences in copy number for each probe in comparison to the control
* basically, 2 different samples with different dyes and mix them. ID the gene looking at, see if more or less or same amount.
what can you see with comparative genomic hybridization?
increased or decreased number of copies of gene of interest. (something absent or extra)
what can you NOT see with comparative genomic hybridization?
balanced abnormalities - aka balanced translocation because test relies on difference in genetic content in numbers between patient and normal
how many chromosomes for haploid
23
how many chromosomes diploid
46
what is polyploid??
multiples of 23 – 69 or 92 chromosomes
characterize triploidy
usually undergo spontaneous abortion, but can survive birth; fetus has problems associated with placenta
what causes triploidy?
2 sperm fertilizing 1 egg – dispermy
what causes tetraploidy?
failure to complete early mitotic divisions in zygote, don’t survive long after birth
what is aneuploidy?
abnormal amount of chromosomes but NOT a multiple of 23 – not a true set of chromosomes, can contain extra chromosome or missing a chromosome
what causes aneuploidy?
nondisjunction during anaphase I or II during meiosis or anaphase of mitosis
what is monosomy?
there is only 1 copy of a particular chromosome in the zygote
which is the ONLY VIABLE FORM OF MONOSOMY
X chromosome monosomy
what is trisomy
3 copies of a particular chromosome in the zygote, most nonviable
which are the only 3 trisomy conditions that are viable?
13, 18, 21
what is nondisjunction of chromosomes?
mis-segregation of chromosomes during anaphase
what causes nondisjunction ?
failure of chromosomes to separate or lack of microtubule connections to one kinetochore
result of nondisjunction?
aneuploidy in resulting daughter cells
when does nondisjunction usually occur?
meiosis I
less common in meiosis II
what is trisomy 21?
down syndrome, most common autosomal trisomy in live births
characteristics of downs syndrome
- intellectual disabilities
- GI tract obstruction
- congenital heart defects
- respiratory infections
- predisposition for leukemia and alzheimers
what is trisomy 18?
Edwards syndrome, 2nd most common autosomal trisomy
survival rate of Edwards syndrome?
50% die within the first few weeks of life, less than 10% survive past 1 year
characteristic of Edwards syndrome?
- prenatal growth deficiency
- congenital heart defects
- low survival rate
- intellectual disability
- low set ears, rotated backward
- small mouth and chin
- rounded plantar surface – rocker bottom feet
what is trisomy 13?
patau syndrome
survival rate of Patau syndrome?
very low, less than 10% survive 1st year of life
characteristics Patau syndrome
- cleft lip/palate
- micropthalmia (small, abnormally formed eyes)
- cardiac defects
- polydactyly
diseases nondisjunction of sex chromosomes
- Turner syndrome
- trisomy X
- Klienefelter syndrome
- XYY syndrome
what causes Turner syndrome?
monosomy of the X chromosome
karyotype of Turner syndrome
45, X
characteristic of Turner syndrome?
- short stature
- broad, shield like chest
- webbed neck
- gonadal dysgenesis (absence of normal ovaries)
- congenital heart defects
who is affected with Turner syndrome?
ALL AFFECTED ARE FEMALE
who is affected with Klinefelter syndrome?
males
karyotype of Klinefelter syndrome?
47XXY
what is the most frequent aneuploidy of sex chromosomes?
Klienefelter syndrome
when is Klinefelter syndrome detected?
after puberty
characteristics of Klinefelter syndrome?
- tall and thin stature, disproportionately long arms and legs
- hypogonadism and low Testosterone
- underdeveloped secondary sex characteristics
- gynecomastia
- infertility
characteristics of trisomy of x chromosme?
XXX karyotype, affected by females but they usually don’t show abnormal phenotype.
possible characteristics of trisomy of X?
sterility, menstrual irregularity, mild intellectual delay, taller than average
characteristics of 47,XYY syndrome
affected are taller than average males with slightly lower than normal IQ, increased risk of minor behavior disorders, hyperactivity, ADD, and learning disabilities.
types of chromosomal abnormalities?
- chromosomal translocations
- chromosome deletions
- chromosome duplication
- chromosome inversion
what causes chromosomal translocations?
breakage of 2 nonhomologous chromosomes, and exchange of the broken fragments
what are balanced chromosomal translocations?
rearrangement doesn’t produce a loss or gain of chromosome material,
type of balanced translocation
reciprocal translocation, where genetic material of 2 difference chromosomes is mutually exchanged
phenotype of reciprocal translocation
no phenotype associated, because no loss of gain of chromosomes; gametes from person with reciprocal translocation can yield offspring with unbalanced translocation
what are unbalanced chromosomal translocations?
rearrangement causes a gain or loss of chromosome material.
example of translocation that causes CML
BCR-ABL translocation, balanced translocation between 9 and 22
impact of balanced translocation in BCR-ABL
makes philadelphia chromosome, where the fusion point of the chromosome makes a fusion protein made up of BCR with ABL tyrosine kinase, and is always active
how does a Robertsonian translocation occur?
ONLY BETWEEN 2 ACROCENTRIC CHROMOSOMES
mechanism of Robertsonian translocation?
short (p) arms of 2 non-homologous chromosomes are lost and the long arms fuse at the centromere to form a single chromosome
effect on carrier of Robertsonian translocation
no effect, because short arms don’t contain essential genetic material
karyotype of Robertsonian translocation carrier
45 chromosomes (bc 2 fused)
what common condition could be caused by a Robertsonian translocation?
downs syndrome! 3 copies of 21 q arm, which mimics consequences of trisomy of the full chromosome 21
example of chromosome translocation
Robertsonian translocation, downs syndrome
example of chromosome deletions
- Cri-du-chat syndrome
- wolf-hirschhorn syndrome
- DiGeorge syndrome (22q11)
- williams syndrome
characteristics of Cri-du-chat syndrome
- laryngeal defects that cause cat-like, high pitched cries.
- intellectual disability (IQ 35)
- microcephaly
- characteristic but not distinctive facial appearance
deletion that causes Cri-du-chat?
deletion of distal end of short arm of chromosome 5 (contains genes important for development)
deletion that causes Wolf-hirschhorn syndrome?
short arm 4p16 close to the centromere
facial characteristics of Wolf-hirschhorn syndrome
- broad flat nasal bridge
- high forehead
- widely spaced eyes
- shortened distance between nose and lip
- downturned mouth
characteristics of wolf-hirshhorn syndrome
- delayed growth and development
- failure to thrive
- hypotonia
- short stature
- skeletal and dental abnormalities
- cleft palate
- intellectual disability
- strong social skills with weak verbal skill
what is most common microdeletion?
DiGeorge syndome! deletion in 22q11
deletion in DiGeorge syndrome?
22q11
effect of deletion of 22q11
defective embryonic migration of neural crest cells to developing structures of the neck, leading to functional defects of thymus, hypoparathyroidism and hypocalcemia
characteristics of DiGeorge syndrome
- hypoparathyroidism
- hypocalcemia
- 80% heart defects
- cleft palate
- functional defects of the thymus
- developmental delay, ADD, anxiety, autism spectrum disorder
2 of the microdeletion syndromes?
- Digeorge syndrome
2. williams syndrome
deletion in Williams syndrome?
delted region contains elastin gene ELN and LIMK1
what is the effect of the ELN deletion in Williams syndrome?
CV defects due to large amount of elastin in the blood vessels
what is the effect of the LIMK1 deletion in Williams syndrome?
LIMK1 is kinase expressed in brain, so have visual spatial deficiencies
characteristics of Williams syndrome
- CV defects
- poor visuospatial abilities
- mild intellectual disabilities
facial features of williams syndrome
- broad forehead
- short palpebral fissure
- low nasal bridge
- full lips and cheeks
- relatively large mouth
example of chromosome duplication
Charcot-Marie tooth disease
how does chromosome duplication happen
uneven crossing over, making 2 copies of a specific region of DNA, less harmful than deletions and leads to partial trisomy
what defect leads to partial trisomy?
chromosome duplication
alternative name for charcot marie tooth
hereditary motor and sensory neuropathy (HMSN)
what duplication causes CMT type 1A?
duplication on PMP22 gene on chromosome 17
what results from duplication in PMP22 gene?
increased production of PMP22 protein, causing structure and function of myelin sheath to be abnormal
what does PMP22 do?
integral membrane glycoprotein produced by Schwann Cells in the PNS
what is the condition called with increased expression of PMP22?
demyelinating peripheral polyneuropathy
characteristics of CMT?
- slow, progressive muscle weakness and atrophy
- upper extremity ataxia and tremor
- pes cavus (high arch)
what is paracentric inversion?
inversion that does NOT include the region of the chromosome with the centromere
what is pericentric inversion?
inversion that INCLUDES the centromere region of the chromosome
what are chromosomal inversions considered?
balanced rearrangements, because they don’t lose any material
what does inversions lead to?
difficulties with homologous recombination during meiosis
diseases caused from chromosome inversions
HEMOPHILIA A
explain hemophilia A
X linked recessive, mutations in gene for clotting factor VIII. hemarthroses, hemorrhages, bruising, intracranial hemorrhages
what is a ring chromosome?
chromosome undergoes 2 breaks, which rearrange and fuses its own broken ends together to form a ring – super rare and unstable
Ring chromosome 14 syndrome characteristics
seizures, intellectual disability, delayed cognitive and motor development, slow growth, short stature, microcephaly, lymphedema
what is an isochromosome?
chromosome separates perpendicular to the axis of cell division, resulting in isochromosomes consisting soley of 2 copies of 1 arm (either p or q arms only)
what does having an isochromosome lead to?
partial trisomy and partial monosomy
what is the most common isochromosome?
long arm of chromosome X (turner syndrome)
what is XP isochromosomes?
duplication of the long arm and no short arm (p), so it looks like a monosomy to the cell
what does XP isochromosome lead to?
20% of the time, Turner syndrome
what does 45XY, der(13;14) mean
a translocation has occurred (derivative)
