Cytogenetics Flashcards
Homologous chromosomes/homologues
Members of a pair of chromosomes that carry the same genes in the same sequence; one inherited from mom and one from dad
Alleles
Slightly different forms of the same gene
Chromatin
Genomic DNA complexed with proteins
Sister chromatids
Created in the S phase of the cell cycle when chromosomes replicate; each contains an identical copy of the original DNA strand
Telomeres
Specialized repetitive DNA sequences that ensure the integrity of the chromosome during cell division
Centromere
A region of DNA that hold two sister chromatids together
Daughter chromosomes
Separated sister chromatids
Recombination: when does it happen and what happens?
Occurs in meiosis I when homologous segments of DNA are exchanged between non-sister chromatids of a pair of homologous chromosomes
Meiosis I separates…
homologous chromosomes
Meiosis II separates…
Sister chromatids
Nondisjunction
When a pair of homologous chromosomes fails to separate during anaphase of meiosis I
The most common chromosomal mechanism of aneuploidy
Percentage of parents with karyotype alterations that impact fertility
1%
Acrocentric chromosomes (#s)
13, 14, 15, 21, 22
Live birth incidence of Down syndrome
1 in 691
Trisomy 21 (Down syndrome) features
Brushfield spots, hypotonia, flat occiput, epicanthic folds, upslanted palpebral fissures, small low set ears, low nasal bridge, maxillary hypoplasia, narrow palate, broad neck (often webbed), CHD (50%, AVSD most common), umbilical hernia, clinodactyly of fifth finger, single palmar crease, sandal toe gap, cryptorchisism (occasional), DD, duodenal atresia, tracheoesophageal fistula, increased risk of leukemia
Pallister Killian syndrome features
Hypotonia, ID, sparse hair, coarse facies, hypopigmented areas of the skin, depressed nasal bridge, down turned mouth, thin upper lip, microcephaly, ptosis
Trisomy 18 (Edwards syndrome) features
FTT, prominent occiput, HYPERtonia, micrognathia, rocker bottom feet, clenched fists, CHDs (99%), low set ears, hypoplastic nails, renal anomalies
Trisomy 13 (Patau syndrome) features
scalp defects, CL/P, CHD (88%, often VSD and PDA), holoprosencephaly, iris coloboma/eye abnormalities, micrognathia, polydactyly, polycystic kidneys, clenched fists, rocker bottom feet
Turner syndrome features
Horseshoe kidney, webbed neck, coarctation of the aorta, widely spaced nipples, short stature, rarely fertile, IQ is typically in normal range
Kleinfelter syndrome (XXY) features and incidence
Tall stature, gynecomastia, infertile, obesity common, IQ typically normal or slightly below
1/500 incidence
47, XXX features
Speech delay, slightly lower IQ than siblings, increased risk of infertility, chromosomally normal offspring
47, XYY features
slightly lower IQ than siblings, ?impulsivity, chromosomally normal offspring
% of live births with cytogenetic disorders
% of stillbirths with cytogenetic disorders
% of 1st trimester SABs with cytogenetic disorders
~0.7%
~10%
50%
Clinical indications for chromosome analysis
Problems with early growth/dev. Stillbirth and neonatal death Fertility problems Fam hx of chromosome abnormality Neoplasia (analysis of the tumor itself) AMA pregnancy
Monosomy prognosis
More deleterious than trisomies - generally not viable except for Turner
Pericentric inversions: definition and possible gametes
Include the centromere
Gametes formed may be normal, balanced, or unbalanced
Paracentric inversion: definition and possible gametes
Does not involve the centromere
Gametes formed may be normal, balanced, or inviable
Triploidy: how common is it in conceptions? What is the most common mechanism? What do we see if the extra set of chromosomes is maternal? Paternal?
- Present in 1-3% of recognized conceptions
- Most frequently the result of dispermy
- Extra set of paternal chromosomes = partial hydatidiform mole
- Extra set of maternal chromosomes - SAB earlier in pregnancy
Types of chromosome structural rearrangements (7)
Terminal deletion Interstitial deletion Unequal crossing over Ring chromosomes Isochromsomes Robertsonian translocation Insertion
Most common robertsonian translocations
45% 14, 13
36% 14, 21
6% 22,13
Inv(9)(p11q12) prognosis
The most common inversion, seen in up to 1% of all individuals tested in cyto labs
No known deleterious effects; considered a normal variant
Alternate segregation
Produces gametes with normal or balanced chromosome complement
Adjacent 1 segregation
Homologous centromeres go to separate daughter cells
All gametes are unbalanced
Adjacent 2 segregation
RARE
Homologous centromeres go to the same daughter cell
All gametes unbalanced
How often does 3:1 segregation occur in translocation carries?
Observed in 5-20% of sperm from balanced translocation carriers
Robertsonian translocation carrier potential gametes: How many are viable? what is the risk of a carrier to transmit the translocation to a child?
Causes 6 types of potential gametes, but only 3 are viable (normal, balanced, and unbalanced +21, 18, or 13)
Carrier females: 10-15% risk of transmitting the translocation; carrier males: only a few % risk of transmitting the translocation –> VIABLE GAMETES DO NOT OCCUR IN EQUAL PROPORTIONS
Insertion: definition, how common are insertions?, what is the risk of producing an abnormal child?
A no reciprocal translocation when one segment is removed and inserted into a different chromosome
Relatively rare because it requires three chromosome breaks
Risk of producing an abnormal child up to 50%
Imprinting: when does it occur? what is it’s purpose?
Occurs during gametogenesis
Marks certain genes as having come from mother or father
Prader-Willi syndrome features and mechanisms
Characterized by obesity, obsessive eating habits, small hands and feet, short stature, hypogonadism, and ID
70% have deletion of paternal 15q11-13
30% have maternal UPD
5% have imprinting center defect
Angelman syndrome features and mechanisms
Characterized by dysmorphic facies, short stature, severe ID, spasticity, and seizures
70% have deletion of maternal 15q11-13 11% have mutation in maternal UBE3A gene 3-5% have paternal UPD 5% have imprinting center defect 10-15% Cause unknown
Uniparental disomy: definition, difference between isodisomy and heterodisomy
Presence of two chromosomes inherited from only one parent
Isodisomy if the chromosome is a duplicate
Heterodisomy if both homologues from one parent are present
Beckwith-Wiedemann syndrome features and mechanism
Macrosomia, enlarged tongue, omphalocele, neonatal hypoglycemia, increased risk of tumors (Wilms tumor, hepatoblastoma)
Due to paternal UPD of 11p15
Complete mole: cause, origin of chromosomes, U/S findings
Result of an abnormal pregnancy that arises when a sperm fertilizes an egg with no nucleus and its chromosomes double
46, XX karyotype of all paternal origin
“Cluster of grapes” on U/S with no fetal development
Ovarian teratoma
Benign tumor that arises from abnormal pregnancy where egg duplicates chromosomes
46, XX all of maternal origin
Little to no extraembryonic development (I.e. Placenta)
Partial mole: karyotype, parent of origin
Triploid
2/3 have extra paternal chromosome set
1/3 have extra maternal chromosome set
Cri du Chat features and mechanism
Caused by terminal or interstitial deletion of 5p; critical region is 5p15
Characteristic cry in infants, microcephaly, hypertelorism, epicanthal folds, low set ears, micrognathia, moderate to severe ID, heart defects
Smith Magenis syndrome features and mechanism
ID, delayed speech/language, distinctive facial features, sleep disturbances, behavioral problems (“lick and flip”)
Del 17p11.2
Charcot-Marie-Tooth mecahnism
Dup 17p12
Hereditary neuropathy with liability to pressure palsies (HNLPP) mechanism
Del 17p12
DiGeorge syndrome/velocardiofacial syndrome mechanism and features
Del 22q11.2 - contains ~30 genes; haploinsufficiency of TBX1 (involved in development of pharyngeal system) is implicated in the phenotype
Craniofacial anomalies, ID, heart defects (TOF), increased risk of schizophrenia
22q11.2 copy number syndromes
1 copy - 22q11.2 del/DGS/VCFS
2 copies - normal
3 copies - 22q11.2 duplication syndrome
4 copies - cat-eye syndrome (ocular coloboma, CHDs, craniofacial anomalies, moderate ID)
Pseudoautosomal region
Region of the Xp and Yp chromosome that are essentially identical and undergo homologous recombination in meiosis I
SRY gene: location, function, expression
- Near the pseudoautosomal boundary on the Y chromosome
- Responsible for male sex determination
- Expressed only briefly early in development of germinal ridge as the testis-determining factor
Azoospermia cause
- Del of AZFa, AZFb, or AZFc regions of Y chromosome; del Yq11.2
- AZFc contains DAZ genes (Deleted in AZoospermia)
X inactivation: definition, % of genes that escape it, role of inactive X
- Done at random in all cells with more than one X
- At least 15% of genes escape inactivation (most found on Xp)
- Inactive X: forms a Barr body, expresses XIST RNA
XIST
Gene in the X inactivation center expressed only from the allele on the inactive X; Produces ncRNA
Nonrandom X chromosome inactivation preferentially inactivates… (3 scenarios)
- abnormal X
- normal X when the other X is involved in a balanced translocation with an autosome
- abnormal X when the abnormal X is involved in an unbalanced translocation with an autosome
%age of T21 pregnancies that end in SAB
%age of T18 pregnancies that end in SAB
%age of Turner pregnancies the end in SAB
78% of T21 pregnancies end in SAB
95% of T18 pregnancies end in SAB
99% of Turner pregnancies end in SAB (Accounts for nearly 20% of chromosomally abnormal SABs but less than 1% of chromosomally abnormal live births)
What is the most common mechanism for T21?
90% caused by error in maternal meiosis (mostly meiosis I)
10% due to error in paternal meiosis (mostly meiosis II)
What percentage of T21 is due to a Robertsonian translocation?
4% have a robertsonian translocation involving chromosome 21 (usually with 14 or 22)
What is the RR for T21?
What is the RR for T13?
T21: RR ~1%
T13: RR < 2% even when a parent carries a translocation
What is the cause of Pallister Killian syndrome?
Mosaic 12p tetrasomy, the two additional copies of 12p are in the form of a small additional metacentric chromosome) - Abnormal cells seen only in the skin
What %age of T18 and T13 cases involve a translocation?
20%
What is the M:F ratio in cases of T18?
1:3 M:F ratio
What is the most common cause of Turner syndrome?
More commonly the result of a paternal meiotic error, 60-80% of the time X is from mom
Karyotype(s) in Turner syndrome
50% 45,X
50% other abnormal karyotype
How does the size of a pericentric inversion relate to the viability of offspring?
Larger pericentric inversions are more likely to lead to viable recombinant off spring because the unbalanced sections are smaller
What is the risk for a pericentric inversion carrier to have a child with an unbalanced karyotype?
The risk for a paracentric inversion carrier?
Pericentric: Overall risk to have a child with an unbalanced karyotype is 5-10%
Paracentric: Very low risk of abnormal karyotype in offspring because unbalanced recombinants are typically acentric or dicentric which are inviable
