Cytogenetics Flashcards
What is a contiguous gene syndrome?
The phenotype is attributable to haploinsufficiency for multiple contiguous genes within the deleted region.
Name some examples of contiguous gene syndromes.
Williams syndrome, DiGeorge syndrome, Smith-Magenis syndrome, Azoospermia
T&T p96 has a good table
What are acrocentric chromosomes?
Chromosomes 13, 14, 15, 21 & 22
short arm is made up of stalks and satellites - repetitive DNA
What is aneuploidy?
loss (monosomy) or gain (trisomy) of one or more chromosomes
What is polyploidy?
gain or one or more haploid sets of chromosomes
What is an isochromosome?
chromosome comprised of two copies of the same arm in mirror image of each other
What is the most common mechanism by which trisomy can arise?
Nondisjunction
Nondisjunction accounts for what percentage of Down syndrome?
95%
maternal meiosis I error is by far the most common
What is the recurrence risk of Trisomy 21 in women <30 years?
1-1.4%
What is the recurrence risk of Trisomy 21 in women >35 years?
Age related risk
*double check that it isn’t higher
What is a Robertsonian translocation?
translocation involving the acrocentric chromosomes and breakage in short arms/stalk/satellite or at centromere
A woman is a 21:21 Robertsonian translocation carrier. What is her recurrence risk for a child with Down syndrome?
100%
21:21 translocations are rare so most cases are de novo in the child with a very low recurrence risk (if mom’s karyotype is normal)
(monosomy 21 is lethal which could explain miscarriage or trouble getting pregnant)
What percentage of Down syndrome is caused by translocation?
~4%
What is the most common Robertsonian translocation involving chromosome 21?
14:21
What is the risk for a woman carrying a 14:21 translocation to have a baby with Down syndrome?
10-15%
What is the risk for a man carrying a 14:21 translocation to have a baby with Down syndrome?
1-3%
What percentage of Trisomy 13 phenotype is due to Robertsonian translocation?
20% (higher than Down syndrome)
What is the most common Robertsonian translocation from chromosome 13?
13:14
most common Robertsonian translocation in gen pop (1/1300)
What is the recurrence risk for Patau syndrome (tri 13) for translocation carriers?
der(13;14) carriers: <2% for males and females
How often does triploidy occur?
1-3% of all conceptions
True/False: Triploidy is one of the most common chromosome abnormalities observed in first trimester miscarriage
TRUE
only a small % survive to full term
What is diandry?
two sets of paternal chromosomes in triploidy- moderate growth retardation of fetus, enlarged abnormal placentas
What is digyny?
two sets of maternal chromosomes in triploidy - severe growth retardation of fetus, disproportional body parts with macrocephaly and small truck and limbs, placenta small and non-cystic
What percentage of recognized pregnancies lost in 1st trimester are chromosomally abnormal?
50-60%
What is the most common trisomy associated with miscarriage?
Trisomy 16
What is the single most frequent abnormality in miscarriage?
Turner syndrome, 45X
trisomy is the most common group of abnormalities in miscarriage
What type of collection tube is needed for cytogenetics?
Green top (contains heparin) - need cells to be alive for cell division to analyze chromosomes
What is the risk for birth of an abnormal child of a balanced translocation carrier?
5-30%
plus higher risk of miscarriage or infertility
What is the risk for a de novo balance translocation rearrangement to cause birth defects? Why?
5-10%; breakpoint of translocation could disrupt an active gene (inactivate it), regulatory elements moved too far away, submicroscopic loss or gain of DNA
What are some limitations of CMA?
cannot detect balance translocations, triploidy, low level mosaicism
What is genomic imprinting?
expression of an imprinted gene depends on the sex of the transmitting parent (ie: Prader Willi syndrome and Angelman syndrome)
What is a maternally imprinted gene?
gene inherited from mom is not supposed to be active; need expression of that gene inherited from father for normal developement; without paternal expression in 15q12 Prader Willi syndrome occurs (missing paternal)
What is paternally imprinted gene?
gene inherited from father is not supposed to be active; need expression of that gene inherited from mother for normal developemnt; without maternal expression in 15q12 Angelman syndrome occurs (missing maternal)
What is uniparental disomy?
both homologous chromosomes are inherited from the same parent; normal chromosome number but not bi-parental inheritance; other parent’s chr is not represented
What are three proposed mechanisms of UPD?
- trisomy rescue
- monosomy rescue
- gamete complementation - not common; disomy egg and null sperm
What is trisomy rescue?
lethal trisomy due to non-disjunction, embryo will expel one of the three copies of the trisomic chromosome from a cell; UPD when both chr from same parent are retained
What does methylation do to gene expression?
Turns gene off
What percentage of Turner syndrome conceptions spontaneously abort by 28 weeks?
99%
The Philadelphia chromosome (translocation of chromosomes 9 & 22) is associated with an increased risk for what condition?
CML (chronic myelogenous leukemia); fusion of two genes in translocation creates a new gene, this protein transforms normal cells into cancer cells
What is the most common cause of Prader Willi Syndrome?
70% caused by deletion of 15q12 on the paternally inherited chromosome
25-30% result from maternal UPD
~5% result from a mutation in the imprinting center of the transmitting father (unable to unmethylate his 15q12 in his gametes– no ‘resetting’)–> 50% recurrence risk!
What is the most common cause of Angelman syndrome?
70% caused by maternal deletion of 15q12
10% mutation in maternal copy of UBE3A–> if inherited, potential for 50% RR
10-15% unidentified etiology
~5% paternal UPD
~5% result from a mutation in the imprinting center of the transmitting mother (unable to unmethylate her 15q12 in her gametes– no ‘resetting’)–> 50% recurrence risk!
What percentage of children with T21 have cardiac anomalies?
40%
What would you expect the phenotype of a 45, XX, der(21;21) individual to be?
Normal carrier of a 21;21 robertsonian translocation. –> all children will have T21.
What percentage of children with T13 have cardiac defects?
80%
What percentage of T18 conceptions end in SAB?
~95%
Most triploid pregnancies lost to 1st trimester miscarriage represent _____________
Diandry
Most triploid pregnancies that survive to term represent _________
Digyny
What tends to be more viable for the offspring of balanced translocation carriers– partial monosomy or partial trisomy?
Partial trisomy. Monosomies generally less viable than trisomies.
CMA shows monosomy for the 5p region… what findings do you expect to see in this child and what is the most likely RR to the parents?
5p minus= Cri du Chat
Expected findings: microcephaly, down-slanting eyes, epicanthic folds, hypertelorism, low set ears, hypotonia, micrognathia, cat like cry, ID… major malformations uncommon.
89-90% are de novo in origin. So MOST likely RR is <1%.
However, 10-11% are the result of a parental structural rearrangement of chromosome 5 (either translocations involving 5p or peri/paracentric inversions of parental chromosome 5)
Other than heart defects, what might comprise the 22q phenotype?
(all variable) cleft palate, immunodeficiency (related to hypoplasia of the thymus), neonatal hypocalcemia (related to parathyroid hypoplasia), ID/LD, psych issues
What percentage of Turner syndrome is 45,X?
50%
(25% are mosaic with 45,X/46,XX as the most common complement)
(25% result from a structurally abnormal X such as del Xp, del Xq, ring X, or isochromosome X)
Why is the likelihood of maternal cell contamination decreased after culturing?
Blood cells do not attach to culture vessels and are NOT induced by mitogens to divide
