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PBL Test 2 - Genetics: Cytogenetics
The chromosomal basis of human disease
159
Medical
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10/29/2010
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Term
Chromosome abnormalities are present in about 1/____ live births.
 Definition
150
Term
Chromosome abnormalities are the leading cause of both ______________ and ____________.
 Definition
Mental retardation and pregnancy loss.
Term
Chromosome abnormalities are seen in what percentage of first and second trimester spontaneous abortions?
 Definition
50% and 20%
Term
What 3 main techniques has improved the visualizations of chromosomes (starting in the 1950s)?
 Definition
spindle poisons to arrest cells in metaphase, hypotonic solutions to swell nuclei, and staining techniques to bring out the chromosome banding patterns
Term
What special features are seen on the short arms of acrocentric chromosomes?
 Definition
Stalks and satellites
Term
What does 14q32.3 refer to?
 Definition
The 3rd sub-band, of band 2, of the third region of the long arm of chromosome 14.
Term
What was the first banding stain?
 Definition
Quinacrine staining
Term
What is the most popular banding stain, and what must be done before its application?
 Definition
Giemsa staining (G-banding), applied after chromosomes are partially digested by trypsin
Term
What is reverse banding and what is it good for?
 Definition
It requires heat treatment and reverses the typical black and white banding patterns, helpful for the distal ends of chromosomes.
Term
What stains the constitutive heterochromatin which usually lies near centromeres?
 Definition
C-banding
Term
What does NOR staining do?
 Definition
highlights the stalks and satellites of acrocentric chromosomes
Term
What type of banding is used to look for a specific, subtle chromosomal abnormality?
 Definition
High-resolution banding, done during prophase or early metaphase, increases observable bands to as many as 800.
Term
What is FISH?
 Definition
Fluorescent in-situ hybridization, labeled probe is hybridized with chromosomes and observed under fluorescence microscope for added, deleted or rearranged material
Term
What is spectral karyotyping?
 Definition
Different fluorescent probes are used to paint chromosomes, very helpful for rearrangements.
Term
What is comparative genomic hybridization, CGH?
 Definition
A test source of DNA is labeled one color, a normal control DNA source is labeled another, they are hybridized to normal metaphase chromosomes. Especially helpful in scanning for deletions or duplications in cancer cells.
Term
A cell with a number of chromosomes that is a multiple of 23 is said to be...
 Definition
euploid
Term
_______ is the presence of a complete set of extra chromosomes in a cell.
 Definition
Polyploidy
Term
Triploidy is seen in 1/_____ live births, and accounts for ___% of chromosomal abnormalities occurring at conception.
 Definition
10,000, 15%
Term
What is the most common cause of triploidy?
 Definition
Fertilization by two sperm, dispermy
Term
The fusion of an ovum and polar body and subsequent fertilization by a sperm would cause...
 Definition
triploidy
Term
Meiotic failure, in which a diploid sperm or egg is produced, could produce which zygotic condition?
 Definition
triploidy
Term
A mitotic failure in the early embryo, in which all the duplicated chromosomes go to one daughter cell, could cause what condition in the zygote?
 Definition
tetraploidy
Term
The fusion of two diploid zygotes could cause...
 Definition
tetraploidy
Term
What does aneuploid refer to?
 Definition
A cell that does not contain a multiple of 23 chromosomes.
Term
In terms of live births, compare autosomal monosomies to trisomies?
 Definition
Only a few monosomies have been observed among live births, trisomies are more common
Term
What is the most common cause of aneuploidy?
 Definition
Non-disjunction
Term
Nondisjunction can cause offspring to have what condition(s)?
 Definition
Monosomy or trisomy
Term
What is the most common aneuploid condition compatible with survival?
 Definition
Down syndrome, trisomy 21
Term
Trisomy 21 is seen in 1/____ live births.
 Definition
800
Term
Who originally described Down syndrome, and when?
 Definition
John Langdon Down, 1866
Term
Describe the typical features of Down syndrome.
 Definition
Low nasal bridge, upslanting palpebral fissures, epicanthic fold, small and sometimes overfolded ears, flattened maxillary and malar region, round cheeks, corners of the mouth are sometimes downturned, short neck, redundant nuchal fold, flat occiput, broad and short hands and feet, simian crease in 50%, hypotonia (highly consistent)
Term
Which types of GI issues will develop in 3% of infants with trisomy 21?
 Definition
Duodenal obstruction, atresia of esophagus, duodenum or anus.
Term
Common respiratory infections and an increased risk of leukemia (15-20x) are seen in children with which condition?
 Definition
Trisomy 21
Term
What proportion of children with Down syndrome are born with structural heart defects?
 Definition
40%
Term
What is the most common heart defect in children with Down syndrome, and what does it cause?
 Definition
AV canal, the septa failed to fuse so blood flows from left to right side of the heart, then to pulmonary vasculature, producing pulmonary hypertension
Term
Ventricular septal defects are common among babies with...
 Definition
Down syndrome
Term
Which condition accounts for 10% of all cases of mental retardation in the US?
 Definition
Down syndrome, moderate to severe retardation is seen in most individuals (IQ of 25-60)
Term
In young children with Down syndrome, what are some of the most important health issues to watch for?
 Definition
Conductive and sometimes neural hearing loss, hypothyroidism, various eye abnormalities
Term
It is estimated that __% of children with Down syndrome will survive to age 10.
 Definition
75% - 80%
Term
Males with Down syndrome are nearly always...
 Definition
sterile
Term
Some females with Down syndrome can reproduce, although approx. __% fail to ovulate.
 Definition
40%
Term
Approx. __% of trisomy 21 conceptions are spontaneously aborted.
 Definition
75%
Term
Approx 95% of Down syndrome cases are caused by ______. About 75% of the time, this occurs during _______.
 Definition
nondisjunction, meiosis 1.
Term
Mosaicism is seen in approx. __ - ___% of trisomy 21 live births.
 Definition
1 - 3%
Term
What would the notation look like for a male with trisomy 21 mosaicism?
 Definition
47,XY,+21/46,XY
Term
What is the most common cause for mosaicism of a trisomy?
 Definition
trisomic conception followed by loss of the extra chromosome during early mitosis of the embryo
Term
The occurrence of germ-line mosaicism trisomy 21 helps account for the recurrence risk for Down syndrome among mothers under 30 yrs old, which is __%.
 Definition
1%
Term
What is the critical portion of chromosome 21 responsible for Down syndrome?
 Definition
21q22
Term
Which hormone(s) should be measured annually in kids with Down syndrome?
 Definition
Thyroid hormones
Term
Why should imaging studies be done in older kids with Down syndrome who want to participate in athletic activities?
 Definition
Instability of the first and second vertebrae has led to spinal cord injuries in some
Term
The cause of mental retardation in Down syndrome has been localized to which gene in the critical region?
 Definition
DYRK
Term
APP encodes which protein? What does it cause?
 Definition
amyloid beta precursor protein, triple copy is likely to account for Alzheimer-like dementia in nearly all Down syndrome pts by age 35-40. (mutations in this gene also cause a small number of Alzheimer disease cases)
Term
Which trisomy is also known as Edwards syndrome? Of autosomal trisomies, how common is it? What is the incidence among live births?
 Definition
Trisomy 18, second most common, 1/6000
Term
Describe the incidence of Edwards syndrome among stillbirths with congenital malformations.
 Definition
It is the most common chromosome abnormality among stillborns with congenital malformations, therefore it is much more common at conception than among live births
Term
Which chromosomal abnormality causes prenatal growth deficiency, characteristic facial features, distinctive hand abnormality, small ears with unraveled helices, small mouth that can be hard to open, short sternum, short big toes, heart defects, omphalocele, diaphragmatic hernia and occasionally spina bifida?
 Definition
Trisomy 18
Term
Those with __________ who survived infancy have marked developmental infancy and most are not able to walk.
 Definition
Trisomy 18
Term
More than 95% of those with Edwards syndome have a complete _________. Small percentage have _______.
 Definition
trisomy 18, mosaicism
Term
As in trisomy 21, there is a significant maternal age effect with ________, and approx 90% of these cases are the result of an extra chromosome contributed from the _________.
 Definition
Trisomy 18, mother
Term
This condition, also called Patau syndrome, is seen in about 1/______ births.
 Definition
Trisomy 13, 1/10,000
Term
The malformation pattern in this condition is distinctive for oral-facial clefts, micropthalmia, postaxial polydactyly, malformations of the CNS and cutis aplasia.
 Definition
Trisomy 13
Term
The survival rate for _________ is similar to that for Trisomy 18, with ____% of pts dying within the first year of life.
 Definition
trisomy 13, 90%
Term
As in trisomy 18, those with trisomy 13 who survive infancy have significant...
 Definition
developmental retardation
Term
About __% of causes of Patau syndrome have a full ______. Most of the remaining cases have ______ of the ____ arm of chromosome ___ due to a translocation.
 Definition
80, trisomy 13, trisomy, long, 13
Term
The risk of bearing a child with trisomy 13 increases with...
 Definition
advanced maternal age
Term
Is it estimated that ___% or more of trisomy 13 and 18 conceptions are spontaneously lost during pregnancy.
 Definition
95
Term
Among mothers under the age of 30, the risk of Down syndrome is less than 1/_____. At age 35, it is 1/____. At age 40, 1/____. After age 45, 1/____.
 Definition
1,000, 400, 100, 50
Term
Approximately ___% of children with Down syndrome are born to mothers under the age of 35.
 Definition
75%
Term
Describe the paternal age affect for trisomies.
 Definition
If it exists at all, it is minor.
Term
Among live births, about 1/___ males and 1/___ females have some form of sex chromosome aneuploidy.
 Definition
400, 650
Term
What is Turner syndrome? What are the major findings?
 Definition
45,X. 1) proportionate short stature, 2) sexual infantilism and ovarian dysgenesis, 3) pattern of major and minor malformations
Term
What syndrome causes a triangle-shaped face, posteriorly rotated external ears and a broad webbed neck?
 Definition
Turner sydrome
Term
What do infants with Turner syndrome sometimes display on the hands and feet?
 Definition
Lymphedema
Term
What defects of vital organs are seen in Turner syndrome?
 Definition
Congenital heart defects, structural kidney defects
Term
Describe the mental retardation of Turner syndrome.
 Definition
Pts are not mentally retarded.
Term
Girls with Turner syndrome do not undergo an adolescent ______________. Instead of ovaries, they usually have ________. They usually do not develop _____________, but can be treated with _________ for this.
 Definition
growth spurt, connective tissue streaks, secondary sexual characteristics, estrogen
Term
Chromosomal abnormalities of Turner syndrome are quite variable, ___% to ___% are mosaics, most commonly ________ and less commonly _______.
 Definition
30-40%, 45,X/46,XX, 45,X/46,XY
Term
Turner syndrome mosaics who have ___ chromosomes in some cells are predisposed to developing _____________.
 Definition
Y, malignancies of gonadal streaks
Term
About 10-20% of pts of Turner syndrome have structural abnormalities of the X chromosome involving a...
 Definition
deletion of some or all of the short arm.
Term
Approx 80% of monosomy X cases are caused by meiotic error in the...
 Definition
father.
Term
Only about 1/2500 to 1/5000 live born females have this disorder.
 Definition
Turner syndrome
Term
The 45,X karyotype accounts for ___% to ___% of the chromosome abnormalities seen among spontaneous abortions.
 Definition
15 to 20%
Term
What percentage of 45,X conceptions are lost prenatally?
 Definition
99%
Term
What type of mosaicism is especially common among 45,X pts who survived to term?
 Definition
confined placental mosaicism
Term
In Turner syndrome, mutations in the ______ gene produce short stature. It's located at the distal tips of the __ and __ short arms (the _________ region).
 Definition
SHOX, X and Y, pseudoautosomal
Term
How do females with Turner syndrome who received the X chromosome from their father differ from those who got it from mom?
 Definition
Higher verbal IQ scores and better social cognition
Term
The imprinted region of the X chromosome escapes...
 Definition
X inactivation
Term
What is the karyotype of Klinefelter syndrome? What is the incidence among births of the correct gender?
 Definition
47,XXY, 1/1000 male births
Term
Klinefelter syndrome is a primary cause of _________________ in this gender.
 Definition
Primary hypogonadism
Term
Males with this syndrome tend to be taller than average, have disproportionately long arms and legs, small testes, sterility from atrophy of seminiferous tubules and gynecomastia.
 Definition
Klinefelter syndrome
Term
Describe the intellect of those with 47,XXY.
 Definition
Predisposition or learning disabilities and sub-average intelligence, but pts are not usually mentally retarded
Term
The extra X chromosome in 47,XXY comes from the mom in ___% of cases, and the condition increases with increased maternal age.
 Definition
50
Term
Mosaicism is seen in about __% of pts with Klinefelter syndrome.
 Definition
15
Term
At least __% of conceptions with 47,XXY are spontaneously aborted.
 Definition
50
Term
With each extra X chromosome, what increases?
 Definition
degree of mental deficiency and physical abnormality
Term
What kind of therapy can enhance secondary sex characteristics in males with ______ syndrome?
 Definition
testosterone, Klinefelter
Term
The ________ karyotype occurs in approx 1/1000 females and usually has a benign phenotype.
 Definition
47,XXX (trisomy X)
Term
Trisomy X females sometimes suffer from...
 Definition
sterility, menstrual irregularity, mild mental retardation
Term
The great majority of cases of trisomy X are the result of _________ in the ________.
 Definition
nondisjunction, mother
Term
Males with this karyotype tend to be taller than average and have subaverage intelligence. Incidence in male prison populations was shown to be greatly increased compared to the general population.
 Definition
47,XYY
Term
Describe the behavioral problems associated with 47,XYY syndrome
 Definition
hyperactivity, ADD, learning disabilities, no evidence for inclination to commit violent crimes
Term
About 1/__ pregnancies are lost after implantation.
 Definition
3
Term
What is the leading known cause of pregnancy loss?
 Definition
chromosome abnormalities
Term
A minimum of __% to __% of conceptions have a chromosome abnormality. At least __% of these are lost before term.
 Definition
10 - 15, 95%
Term
Studies of miscarriages show that about 50% of the chromosome abnormalities are _________, 20% are _______, 15% are _________, and the remainder consist of ______ and ______.
 Definition
trisomies, monosomies, triploids, tetraploids and structural abnormalities
Term
Trisomy __ is thought to be the most common trisomy at conception, but it is never seen in live births
 Definition
16
Term
Balanced structural abnormalities of chromosomes often do NOT produce...
 Definition
serious health consequences
Term
Alterations of chromosome structure can occur when chromosomes ___________ improperly during meiosis, or ________ during mitosis or meiosis.
 Definition
line up, break
Term
What is the term for an agent that increases the likelihood of chromosome breakage?
 Definition
clastogen
Term
The interchange of genetic material between nonhomologous chromosomes is called...
 Definition
translocation
Term
What are the two main types of translocations?
 Definition
Reciprocal and Robertsonian
Term
The chromosome that results after a translocation involving equal exchange is called a...
 Definition
a derivative chromosome
Term
What consequence is a reciprocal translocation to the carrier? What about to the offspring?
 Definition
Carrier is usually normal, offspring can be normal, carry the translocation or have duplications or deletions
Term
What happens during a Robertsonian translocation?
 Definition
The short arms of two nonhomologous chromosomes are lost and the long arms fuse at the centromere.
Term
Robertsonian translocation is confined to which chromosomes? Why?
 Definition
13, 14, 15, 21, and 22 - they are acrocentric and have very small short arms with no essential genes
Term
Carriers of a Robertsonian translocation are phenotypically normal but have only ___ chromosomes in each cell.
 Definition
45
Term
A Robertsonian translocation can involve the fusion of the long arms of chromosomes 21 and 14. What would the karyotype of a male carrier be?
 Definition
45,XY,-14,-21,+t(14q21q)
Term
Carriers of a Robertsonian translocation can have what two types of segregation during gametogenesis?
 Definition
alternate or adjacent segregation
Term
If alternate segregation occurs during gametogenesis, what is the consequence to the offspring?
 Definition
Either chromosomally normal or have a balanced translocation with normal phenotype
Term
If adjacent segregation occurs during gametogenesis, what is the consequence to the offspring?
 Definition
offspring have have trisomy or monosomy of either chromosome involved in the translocation
Term
Robertsonian translocations are responsible for approx __% of ______ syndrome cases.
 Definition
5, Down
Term
Why should a karyotype be done on a child who has Down syndrome with 100% certainly based on clinical presentation?
 Definition
Recurrence risk for Down syndrome from Robertsonian translocation is greater than the non-disjunction type of Down syndrome, but the phenotype is the same
Term
A break leading to the loss of a chromosome's tip is called a ...
 Definition
terminal deletion
Term
When two breaks occur in a chromosome and the material between them is lost, it is called a....
 Definition
interstitial deletion
Term
Which syndrome is caused by a deletion of the distal short arm of chromosome 5 (46,XY,del[5p])?
 Definition
Cri-du-chat syndrome
Term
Cri-du-chat is seen in approx 1/_____ live births, and is characterized by...
 Definition
50,000, mental retardation, microcephaly, characteristic facial appearance
Term
What causes Wolf-Hirschhorn syndrome?
 Definition
Deletion of the distal short arm of chromosome 4
Term
75% of Prader-Willi syndrome cases are caused by a microdeletion of which arm of which chromosome?
 Definition
15q
Term
Microdeletion of paternal 15q results in ________, and of materal 15q results in _________.
 Definition
Prader-Willi syndrome, Angelman syndrome
Term
WAGR syndrome can be produced by a deletion of 11p, and produces what main 4 features?
 Definition
Wilms tumor, aniridia, GU abnormalities, mental retardation
Term
When a structural defect involving a series of adjacent genes produces a particular syndrome, it is called a __________ syndrome.
 Definition
contiguous gene syndrome
Term
Which syndrome is characterized by mental retardation, supravalvular aortic stenosis, multiple peripheral pulmonary arterial stenosis, chacteristic facial features, dental malformations and hypercalcemia? What type of syndrome is it?
 Definition
Williams, a microdeletion syndrome
Term
Which gene is located in the Williams syndrome critical region and is expressed in blood vessels?
 Definition
elastin
Term
Which gene in the critical region is likely to be involved in the visual-spatial cognition defects in Williams syndrome patients?
 Definition
LIMK1
Term
Deletion syndromes may be caused by multiple repeated sequences at the deletion boundaries, which promote...
 Definition
unequal crossing over, which then produces deletions
Term
A condition in which one parent has contributes two copies of a chromosome and the other parent has contributed no copies is called...
 Definition
uniparental disomy
Term
What is it called when one parent contributes two copies of one homolog to the offspring?
 Definition
isodisomy
Term
What is it called when one parent contributes one copy of each homolog of a chromosome to the offspring?
 Definition
heterodisomy
Term
What are the two main mechanisms by which a uniparental disomy may arise?
 Definition
trisomic conception followed by loss of one of the extra chromosomes, monosomic conception followed by mitotic nondisjunction
Term
Uniparental disomy has been observed mainly in which syndromes?
 Definition
cystic fibrosis, Prader-Willi and Angelman, Beckwith-Wiedemann
Term
What are the two main mechanisms by which duplications arise?
 Definition
Unequal crossover or from reciprocal translocation in the parent
Term
How does a ring chromosome happen?
 Definition
Deletions at both tips of the chromosome, fusing of the ends
Term
Ring chromosomes are often _____, resulting in _________ in at least some cells.
 Definition
lost, monosomy
Term
A chromosomal inversion is the result of...
 Definition
two breaks followed by reinsertion of the segment in an inverted order
Term
What are the two main types of inversions?
 Definition
pericentric and paracentric
Term
What is the consequence of an inversion for the carrier? The offspring?
 Definition
Seldom produce disease in the carrier, can produce abnormalities in offspring - often have deletions or duplications
Term
It is estimated that about 1/____ people carries an inversion.
 Definition
1000
Term
What results when a chromosome divides along an axis perpendicular to its usual axis of division?
 Definition
an isochromosome
Term
What is different about an isochromosome?
 Definition
it has two copies of one arm of a chromosome and no copies of the other arm
Term
Most isochromosomes observed in live births involve the __ chromosome.
 Definition
X
Term
A pericentric inversion causes the formation of a _____ during the alignment of homologous chromosomes in meiosis.
 Definition
loop
Term
46,X,i[Xq] individuals usually have features of ________ syndrome.
 Definition
Turner
Term
What are the 4 main features that most chromosome abnormalities will display?
 Definition
developmental delay or mental retardation, facial morphogenic alteration, growth delay, congenital malformations
Term
What are the most common clinical indications for chromosome analysis in the newborn? In the child?
 Definition
multiple congenital malformations, developmental retardation
Term
CML commonly involves what chromosomal abnormality? What is the resultant chromosome called?
 Definition
Reciprocal translocation between chromosomes 9 and 22, Philadelphia chromosome
Term
What is the mechanism by which the CML chromosome abnormality produces a defective gene?
 Definition
proto-oncogene abl is moved from 9q to 22q, alters the protein product, exhibits increased tyrosine kinase activity
Term
What type of cancer is common in Africa and is associated with a translocation? What is the translocation? What effect does it have?
 Definition
Burkitt lymphoma, reciprocal translocation involving 8 and 14, moves myc proto-oncogene near the IG heavy chain loci, causes activation of myc
Term
Some autosomal recessive diseases cause increased incidences of chromosome breaks, these are called _______________ syndromes.
 Definition
chromosome instability syndromes
Term
Name several chromosome instability syndromes
 Definition
ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, xeroderma pigmentosa
Term
The chromosomal instability syndromes are associated with increased _________ risk.
 Definition
cancer
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