LEC42: Inborn Errors of Development: Chromosomes and Cytogenetics Flashcards
cytogenetics?
study of chromosomes
mechanisms of chromosomal disorders (microscopic & submicroscopic)
what proportion of 1st trimester spontaneous abortions do chromosome abnormalities cause?
2/3
what % of cardiac defects do chromosome abnormalities cause?
20% of pts w/ cardiac defects
what % of individuals w/ intellectual disability have a chromosomal abnormality?
individiuals w/ autism and cardiac defects?
intellectual disability: 20-30%
autism, cardiac defects: 20% each
characteristics to identify chromosomes?
size, banding pattern, position of the centromere
how are chromosomes numbered?
based on length, 1 is longest, 22 should be shortest (actually, 22 is longer than 21)
chromosome nomenclature:
short arm?
p
chromosome nomenclature:
long arm?
q
chromosome nomenclature:
region?
counting outward from centromere
within each region, have bands
chromosome nomenclature:
landmark?
consistent & distinct morphologic features
chromosome nomenclature:
bands?
division of regions
centromere is?
telomere is?
centromere: central condense region essential for itotic spindle attachment
telomere: terminal cap at end of each chromosome
what does p11.1 mean
p is short arm
1 is chromosome
2nd is region
3rd is subband
name parts of the chromosome/their function
short arm: p
long arm: q
telomere: cap/end of chromosome, helps chromosome keep its integrity; shortens with aging
subtelomeric region: region most prone to errors of deletions and duplications
center: centromere; different centromere locations can characterize diff chromosomes
metacentric vs. sub-metacentric vs. acrocentric chromosome?
metacentric: centromere in middle of equal p and q arms
sub-metacentric: p short, q longer
acrocentric: p arm essentially a satellite, doesn’t do much
what are dark/light bands on chromosomes?
dark: heterochromatin, inactive in transcription, not expressed, long repeats of many genes, thus more variable regions
light: euchromatin, more active txn area, where most active genes and crucial human disease genes are
which chromosomes have large heterochromatic regions?
1, 9, 16, Y
which chromosomes are acrocentric?
13, 14, 15, 21, 22
p arm is a satelle, nub, does not have important function - could lose satellite to no consequence for function
when in cell cycle can chromsomes be visualized?
metaphase
during active division
which cell types provide easy chromosome visualization?
dividing cells, in mitosis of cell cycle:
**T lymphocytes in blood which divide by phytohemagglutinin **
bone marrow cells
**fibroblasts from skin biopsies **
prenatal chorionic villi and fetal cells in amniotic fluid
products of conception (placental & fetal)
in what part of cell cycle do cells spend most of their time?
interphase
how long is cell cycle?
mitosis?
cell cycle: 24 hours
mitosis: 1-2 hours
what is chromosomal imbalance?
when is it most common?
imbalane in the amount of chromosomal material; may involve a few to 1000s (partial/whole chromosome) of genes, have catastrophic effects
most common in spermatogenesis, oogenesis
how can chromosomal imbalance mainfest?
1) whole or partial aneuploidy: gain or loss of a whole chromosome
2) abnormality may be in constitutional, non-mosaic, or mosaic state, which is less severe, = various chromosome complements in different cells
3) monosomy - one missing - is more devastating than trisomy - one extra
clinical phenotypes of chromosomal abnormalities
1) development delay/intellectual disability
2) alteration of facial morphogenesis to produce characteristic facial features
3) growth delay
4) malformations of internal organs - esp. cardiac
general effects of structural and numerical abnormalities - how do 1) loss of genetic material, 2) gain of genetic material, 3) relocation manifest?
1) loss of genetic material: deletion/monosomy
2) gain of genetic material: duplication/trisomy
3) relocation of genetic material: inversion/insertion/translocation
first trimester abortuses are mostly what kind of abnormality?
what kind of chromosomal abnormality dominates when fetus is born?
1st trimester: numerical - extra or missing chromosome, not structural issue
when fetus born: balanced/unbalanced abnormalities
why do chromosomal abnormalities occur more commonly in older than in younger women?
their eggs have been “frozen in time” for longer
error of nondisjunction more common when oocyte has been suspended for long time
what is most common cause of spontaneous abortions?
what trisomy is observed w/ this?
chromosomal imbalance causes 66% 1st trimester spontaneous abortion, 20% 2nd trimester spontaneous abortions
trisomy 16 most common trisomy observed; never seen in liveborn (except if mosaic)
ploidy?
addition or loss of **complete sets **of chromosomes
euploidy?
normal diploid chromosomal state
triploidy?
its cause?
what happens?
1 complete extra set of chromosomes
caused by polyspermy, fertilization of an egg by more than 1 sperm
usually spontaneously abort
digyny: extra haploid set is fro mmother; get IUGR, v. small placenta
diandry: extra haploid set is from father; get well grown fetus and large cystic complement
tetraploidy?
cause?
what happens?
egg fertilized by 2 sperm
failure of first (early) zygotic division
lethal to embryo
other cell divisions may also fail to complete properly; small proportion of tetraploid cells can be in norma individuals (mosaicism)
what are autosomal numerical abnormalities?
aneuploidy, monosomies, trisomies
aneuploidy?
chromosome changes that don’t involve whole sets
usually consequence of failure of single chromosome (or bivalent) to complete division
problem in chromosomal copy number
monosomies?
only 1 chromosome present in pair
all are lethal in early embryogenesis; abort too early to be recognized as conception
trisomies?
what is risk factor for it?
meiosis I nondisjunction causes this
3 chromosomes instead of 2
incidence of trisomes rises sharply w/ increasing maternal age
which full non-mosaic aneuploides are survivable?
trisomy 13
trisomy 18
trisomy 21
what is nondisjunction?
disjunction: when chromosomes are paired off in middle, split, make 2 gametes
NON disjunction: chromosomal material stuck, 1 gamete has extra chromosome material, leads to a trisomy
what causes trisomy 21
95% caused by **maternal meiosis I nondisjunction **
5% by parent carrying a Robertsonian translocation or mosaicism for Trisomy 21
75% spontaneously aborted
if child has trisomy 18, what kind of gene do they have for it?
must be mosaic
otherwise too severe
= edward’s syndrome
what is more common: sex chromosome or autosome aneuploidies?
sex chrom aneuploidies are more common and less severe than in autosomes
b/c of X-inactivation and paucity of genes on Y chromosome
what is X-inactivation
when females turn off/silence 1 copy of genes on one X chromosome
makes gene dosage of X chromosome similar in males & females
what are pseudoautosomal regions
genes on X-chromosome that’re also present on Y chromosome
these escape X-inactivation
occurs in: turner syndrome, klinefelter syndrome
what is cause of turner syndrome?
incidence?
phenotype?
numerical abnormality causing 45,X - missing an X
very common, but 99% spontaneously aborted
phenotype: nondysmorphic mostly; coarctation of aorta; kidney issues; haplo insufficiency
treatment for turney syndrome?
growth hormone & estrogen
what causes most turner syndrome?
what are diff cytogenetic possibilities?
80% due to paternal meiotic error
45, X 50%
45,X/46,XX or 45,X/46,XY MOSAICS 30-40%
structural X abnormalities 10-20%
what is cause of klinefelter syndrome? cause?
47,XXY
pseuatosomal region abnormality
problems w/ testicular function, decreased sexual characteristics, little spermatogenesis, ADHD
what are 47,XYY males and 47,XXX females
examples of numerical abnormalities of sex chromosomes
both are essentially “normal”
what is >3 copies of X chromosome associated w?
mental retardation
uniparental dipoidy?
results?
when all chromosomes are inherited from 1 parent
if paternal: hydatidiform moles; only get trophoblast hyperplasia, no fetal parts
if maternal: from an activated unovulated oocyte; get ovarian tetroma, disorganized embryonic material
uniparental disomy?
when person receives 2 copies of a chromosome, or of part of a chromosome, from 1 parent, and 0 copies from the other parent
affects single pair of chromosomes
usually causes problems in imprinted genes on specific chromosomes (6, 7, 11, 14, 15, 16)
usual cause is trisomy rescue
what is trisomy rescue?
when fertilized ovum containing 3 copies of a chromosome loses 1 of these chromosomes to form a normal, diploid chromosome complement
if both retained chromosomes came from same parent, get univparental disomy
types of structural rearrangements?
1) translocation
2) inversion
3) deletion/duplication
4) ring chromosome
translocation?
interchange of genetic material between nonhomologous chromosomes
can be reciprocal/balanced: no phenotype usually, only phenotype if have disruption in break point
unbalanced: parital monosomy or partial trisomy - missing or extra piece
what happens in a translocation carrier?
whereas normally sister chromatids line up as bivalent and then get normal chromosome segregation, translocation carriers form a tetrad of chromosomes
during separation or disjunction, get unbalanced translocation
what are adjacent 1 and 2 outcomes?
outcomes of translocation carrier chromosome segregation
adjacent 1: unbalanced translocatoin
adjacent 2: centroemres from the same chromosome
robertsonian translocation?
translocation between different acrocentric chromosomes (13 to 14, for ex)
short arms are lost, long arms fuse at centromere
occurs in 5% of Down Syndrome cases
considered balanced b/c no missing chromosomal material!
inversions?
types?
2 breaks in 1 chromosome
area between the breaks is inverted, then reinserted, the breaks unite then to rest of chromosome; can be terminal- to end of chromosome, or interstitial- within the long or short arm
**pericentric inversion: **if inverted area includes centromere
paracentric inversion: if inverted area doesn’t include centromere
can cause deletions, duplications
what do inversions cause?
deletions, duplications
deletion is?
loss of a chromosome segment
can be interstitial or terminal
wolf-hirschhorn syndrome is ex. of?
deletion of 4p16.3
ring chromosomes?
when pieces on top of chromosmoe fall off, join into a ring shaped chromosome
Ring X r(X) is most common, causes Turney syndrome in most cases
“viable” chromosome imbalances?
unbalanced translocations: partial monosomy & partial trisomy
deletions: partial monosomy
duplications: partial trisomy
ring: partial monosomy
recombinant inversion derivatives: partial monosomy & partial trisomy
what is FISH
FISH = flourescence in situ hybridization
physical DNA mapping technique
DNA probe labeled w/ marker molecule is hybridized to chromosomes on a slide, visualized using flourescence microscope
marker molecule is floursescent or detected w/ fluourescently labeled antibody
FISH hybridization steps?
denature ds DNA, generate single-stranded DNA
probe w/ fluorochrome DNA probe of bases
probe recognizes target DNA sequences
probe hybridizes to target DNA sequences
FISH applications?
chromosome identification
aneuploidy detection in prenatals
marker chromosome identification
total chromsome analysis
translocation analysis
microdeletion syndrome analysis
gene amplification analysis in cancer
what is FISH used to study?
good to est. deletion, duplication of genomic regions too small to be detected by karyotype analysis
particularly: recurrent microdeletion syndromes caused by unequal crossing over events at susceptible regions of the genome
confirmation, not diagnosis of genomic disorders involving microdeletion/duplication syndromes
ie DiGeorge Syndrome - deletion of single gene on 22q11 or Wilms tumor, caused by deletion of series of adjacent genes on 11p13
cause of DiGeorge/Velo-cardio-facial syndrome?
22q11 deletion
array CGH usefulness?
what isn’t it good for?
**genome-wide view of copy number variations **
helps to find cause for selected conditions ie of intellectual disability and multiple congenital anomalies; standard of care used rather than karyotype
cannot detect chromosomal anomalies that mintain normal copy numer (balance translocation, inversions); does not provide data on repeat-rich regions (centromeres, hterochromatin)
what is meiosis?
meiosis I: process by which recombination of chromosomes occurs in germ cells
meiosis II: yields mature haploid oocytes and spermatogonia
why do trisomies/monosomies occur?
failure to properly segregtae chromosomes during each division step of meiosis
leads to abnormal copy number in resulting conceptus
are autosomal numerical abnormalities viable? why/why not?
usually, not
because large alterations in gene dose occur
what causes most trisomies?
95% trisomies are due to meiotic non-disjunction
75% occur during meiosis I
