Chromosome Numerical Abnormalities Flashcards
Term for number of homologous chromosome sets present in a cell or organism
Ploidy (n)
Define human haploidy, diploidy and polyploidy
Haploid = n = 23
Diploid = 2n = 46
Triploidy = 3n = 69
etc.
Define aneuploidy and euploidy
Euploidy - exact multiple of haploid set of chromosomes
Aneuploidy - incomplete haploid set - abnormal chromosome numbers (45, 47 etc)
Most common parent and phase of meiosis for aneuploidy?
Maternal meiosis I
Incidence of ALL chromosome abnormalities in newborns?
1 in 150
Incidence of ALL aneuploidy in newborns?
1 in 250
Incidence of X and Y aneuploidy in newborns?
1 in 475
Incidence of autosome aneuploidy in newborns?
1 in 700
Incidence of balanced structural abnormalities in newborns?
1 in 500
Incidence of ALL structural abnormalities in newborns?
1 in 375
Incidence of unbalanced structural abnormalities in newborns?
1 in 1600
Incidence of trisomy 21 in newborns?
1 in 700 (to 1,000) livebirths
Incidence of trisomy 18 in newborns?
1 in 6000 (to 10,000)
Incidence of trisomy 13 in newborns?
1 in 10,000 (to 16,000)
Most common trisomy in miscarriage?
Trisomy 16 - 80%
___% of sperm and ___% of oocytes show chromosome abnormalities
10% of sperm
20-25% of oocytes - aneuploidy > polyploidy > structural abnormalities
Four tolerated aneuploidies in conceptus?
45,X and trisomies 16, 21 and 22
Three tolerated autosomal trisomies?
13, 18, 21 (also most common cause of stillbirths)
Cause of 95-99% of SABs?
Turner syndrome 45, X
Crossing over occurs in what phase of Meiosis?
Prophase I
4c, 2n
At the end of male meiosis I what is the ploidy?
2c, 1n
haploid with 2 copies
At the end of male meiosis II what is the ploidy?
1c, 1n
haploid with 1 copy
5 phases of prophase I?
leptotene - beginning of chromosome condensation , telomeres touch nuclear membrane
zygotene - homologs pair and synapsis
pachytene - crossing over
diplotene - homologs separate, tethered by chiasma
diakenesis - separation of homologs
Eggs are suspended in which meiosis phase until fertilization?
Prophase I
Extra phase of prophase I in eggs?
dictyotene - stage after pachytene (crossing over)
= male diplotene
Completion of female meiosis occurs when?
After fertilization
How many sister chromatids are involved in each crossover event?
One
1 centimorgan (cM) = ___% chance for recombination
1%
Number of chiasma/chromosome arm required for normal segregation?
1
*typically 46-53 chiasmata total and correlates with length of chromosome arm
Recombination occurs more in males or females?
Females
Recombination occurs more in centromeres or telomeres?
Telomeres
Chance of same exact random segregation of chromosomes?
1 in 2^23 (1 in 8 million)
*recombination makes it even smaller
Define nondisjunction
Failure of homologous chromosomes (MI) or sister chromatids (MII, mitosis) to separate;
Parental origin of trisomy is most often paternal or maternal and what stage of meiosis?
maternal meiosis I
Define heterodisomy
Two copies of the chromosome from the same parent (homologs)
Define the two results of meiosis I nondisjunction
Heterodisomy (same parent homologs)
Nullisomy
Define the result of meiosis II nondisjunction
Isodisomy - two sister chromatids from the same parent
Timing on nondisjunctions in oocytes
14 days before ovulation (meiosis I - first polar body formed)
Hours after fertilization (meiosis II
Mechanism of nondisjunction?
Aberrant recombination
- achiasmate (absent) or reduced recombination
- suboptimal locations of crossovers (pericentromeric)
Premature separation of sister chromatids leads to _____ and _____ gametes
disomic and nullisomic
Parental gamete and stage of meiosis for nondisjunction?
- Oocyte
- Meiosis I
Nondisjunction in postzygotic mitosis leads to ________
Mosaicism
Most common trisomy in early pregnancy loss (<10 weeks)?
Trisomy 16
_____ is a ring-shaped protein complex that organizes the genome, enabling its condensation, expression, repair and transmission. The loss of it results in loss of chiasmata and premature separation.
cohesin
Advanced maternal age
35
Aneuploidy present in _____% of sperm and ______% of eggs
Sperm = 10%
Oocytes = 20-25%
_________ and __________ cause more severe phenotypic consequences than trisomy and duplications
Monosomy, deletions
Sex chromosome abnormalities of live birth?
45, X and 47 XXX and 47 XYY and 47 XXY
____% of 45, X conceptuses are spontaneously aborted
99%
Imbalance of _______ bands (gene‐rich) more severe than _______ bands (gene‐poor)
G-negative (rich)
G-positive (poor)
The tolerated trisomies are gene ______ autosomes
Gene poor
Gautier discovered the first medical condition shown to result from a chromosome abnormality (1959)
Trisomy 21 (DS)
Prevalence of Trisomy 21 in live births?
1 in 800
_____% of Trisomy 21 conceptuses survive until birth
20%
The most common genetic aberration for intellectual disabilities
Trisomy 21
Trisomy 21 features (10)
Hypotonia
Almond‐shaped eyes, epicanthal folds, brushfield spots
Flat nasal bridge
Excess nuchal skin
Single palmar flexon crease; clinodactyly
Cardiovascular defects ‐ 40%
ID
Transient myeloproliferative disorders (MDS) in newborns (associated with
GATA1), and 500-fold higher risk of
leukemia (AML and ALL ~1:1)
Premature dementia (Alzheimer’s disease)
onset 50 yo, due to APP in 21q21.3
Down syndrome critical region
“DS critical region” (DSCR): 21q22.1q22.3
Down syndrome Mechanism (hint 5)
- 85-90% Maternal meiosis (75% Meiosis I, 25% Meiosis II)
- 3-5% Paternal meiosis (II = 75%, I = 25%)
- 4% Robertsonian
- 3-5% Mitosis
- Other
Mechanism of 85-90% of trisomy 21
Maternal meiosis (I (75%) > II (25%)
Recurrence risk for down syndrome with maternal age <30
1%
Three possible explanations for recurrent trisomy 21
- Random
- Parental gonadal mosaicism
- Predisposition to nondisjunction
Nomenclature for robertsonian translocation with chromosome 14 (q10;q10)
46,XX,der(14;21)(q10;q10),+21
Empiric risk for robertsonian translocation (female vs male carriers)?
1/3 empiric risk
10-15%
vs
0-2%
___% of trisomy 21 embryos become mosaic with a nondisjunction event and trisomy rescue during mitosis. Varied phenotype
2%
Risk = ____% for i(21)(q10) except for gonadal mosaicism
100%
Trisomy 18 incidence in live births?
1 in 6,000 (to 8,000)
Trisomy 18 is associated with paternal/maternal meiosis ____
maternal meiosis II
Trisomy 18 phenotype
IUGR
Microcephaly
Omphalocele
Cardiac defects
Severe ID
Clenched hand position w/ 2&5 over 3&4
Clubfoot or rocker-bottom feet
Small, low set ears
Trisomy 13 incidence in live births?
1 in 10,000 (to 16,000)
Trisomy 13 phenotype?
Midline defects:
Holoprosencephaly (failure of brain development) / microcephaly
Cleft lip/palate
Cutaneous scalp defects (cutis aplasia)
Congenital heart defects
Omphalocele
Polydactyly
Renal abnormalities
Severe ID
IUGR
Trisomy 8 mosaic syndrome incidence?
1in 25,000
Trisomy 8 mosaic syndrome name and karyotype?
Warkany syndrome
mos 47,XX,+8/46,XX.
Trisomy 8 mosaic syndrome phenotype?
thick lips
camptodactyly
clinodactyly
deep plantar and palmar skin furrows
ID
vertebral or hip anomalies
joint
kidney
cardiac,
skeletal abnormalities
skin hyper/ hypopigmentation
Males are more frequently affected than females
_______ ______________ two aneuploidy events in the same individual (i.e. Down Syndrome with XXY (Klinefelter))
Double aneuploidy
________ results in 12% of spontaneous abortions and are the result of an additional haploid genome set
Polyploidy
The two exceptions to the mechanism of aneuploidy being nondisjunction in maternal meiosis I?
- Trisomy 16 = meiosis II
- 45, X = paternal nondisjunction
Risk for aneuploidy?
1. Maternal age 35
2. Maternal age 42
- 1 in 350
- 1 in 42
_____ aneuploidy is when only part of the body is involved
mosaic
_____ aneuploidy is when only part of the chromosome is involved
partial
-deletions, duplications and unbalanced translocations
-Pallister Killian Syndrome
Pallister Killian syndrome chromosome
iso 12p
Isochromosomes form by fusion of homologous ______ arms into one chromosome and the fusion of homologous ____ arms
p, q
Isodicentric chromosomes form from the ______ ___________ of one complete arm and partial other arm
Inverted duplication
Cateye syndrome chromosome
Idic (22)
Coloboma of the iris
Anal atresia with fistula
Heart and renal malformation
_______ chromosomes are the result from breaks at both ends of a chromosome or fragment and are sometimes the result of complex inversions, duplications, or deletions with crossing over
Ring
Pallister Killian is a tetrasomy and is always _______
mosaic
Pallister Killian syndrome occurs ____ ________ and has a _______ (high/low) recurrence risk
de novo
low
Pallister Killian syndrome results from Iso 12p and results in the ___________ of 12p
Tetrasomy
Tetrasomy 12p phenotype
Course face
High forehead
Sparse scale hair
Hypertelorism
Epicanthal folds
Severe ID
Hypotonia
Hypopigmented streaks/spots
Accessory nipples
Cardiac anomalies
Diaphragmatic hernia
A small (size < chromosome 20) supernumerary chromosome, whose identity is not determined using classical methodology, is called a ___________ chromosome
marker (mar)
Marker chromosomes usually arrive from __________ chromosomes (____, ______, ______, ______ and _____)
acrocentric (13, 14, 15, 21 and 22)
40 - 70% of marker chromosomes are comprised of chromosome _____??
15 (break points 1 and 2 without PWS or AS)
Small supernumerary marker chromosome incidence in livebirths?
1 in 500
Large inversion duplication of 15 (break points 1-3+) can cause two syndromes, what are they
Prader Willi Syndrome
Angelman syndrome
Large inversion duplication of 15 (break points 1-3+) are usually _______ (paternal/maternal) in origin?
Maternal
Isodicentric (15)/Inv dup 15 occurs in 1 in __________ live births and occurs in a ______ ratio of males to females?
30,000
1:1
Probe for chromosome 15 in the PWS/AS region and further down on the q arm
SNRPN
PML
Isodicentric chromosomes have ______ centromeres
Two
Idic(15) phenotype
Autistic/ID
Hypotonia/lax ligaments
Epilepsy
Facial dysmorphisms (long philtrum, full cheeks, bulbous nose)
**brain abnormalities, GU defects, growth retardation
** congenital heart defects, microcephaly
3 chromosome 22 syndromes?
- DiGeorge
- Cateye syndrome (idic 22)
- Der (22)
Nomenclature for supernumerary and non-supernumerary ring chromosomes that usually arise de novo
47, r
46, r
Pathogenicity prediction = ____% for ring chromosomes
60%
Pathogenicity prediction = ____% for Non-satellited/non-acrocentric marker chromosomes
15%-29%
Pathogenicity prediction = ____% for Satellited/Acrocentric marker chromosomes
0-11%
