Cytogenetics

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Chapter 3

Lecture structure

• Basic definitions and terminology
• Numerical chromosome abnormalities
• Structural chromosome abnormalities
• Other chromosome abnormalities
• Advances in molecular cytogenetics

Overview

• This chapter reviews diseases that are caused by microscopically observable alterations in chromosomes.
• These alterations may involve the presence of extra chromosomes or the loss of chromosomes.
• They may also consist of structural alterations of chromosomes.

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• Chromosome abnormalities are seen in approximately 1 in 150 live births and are the leading known cause of mental retardation.
• The vast majority of fetuses with chromosome abnormalities are lost prenatally:
• Chromosome abnormalities are seen in 50% of spontaneous fetal losses during the first trimester of pregnancy,
• and they are seen in 20% of fetuses lost during the second trimester.
• Thus, chromosome abnormalities are the leading known

cause of pregnancy loss.

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Basic definitions and terminology

Karyotype

• Chromosomes are most easily visualized during the metaphase stage of mitosis, when they are maximally condensed.
• They are photographed under the microscope to create a karyotype, an ordered display of the 23 pairs of human chromosomes in a typical somatic cell.

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• Chromosomes are ordered according to size, with the sex chromosomes (X and Y) placed in the lower right portion of the karyotype.

Photograph of Metaphase Chromosomes (Karyotype) of an individual male.

Karyotype

Human Metaphase Chromosomes. Idealized Drawing (Karyogram), represents a drawing of each type of chromosome; the presentation is haploid (only one copy of each chromosome is shown).

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Chromosome banding

• Metaphase chromosomes can be grouped according to size and to the position of the centromere,
• but accurate identification requires staining with one of a variety of dyes to reveal characteristic banding patterns.
• G-banding. Mitotic chromosomes are partially digested with trypsin

(to digest some associated protein) and then stained with Giemsa, a dye

that binds DNA.

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• G-banding reveals a pattern of light and dark (G-bands) regions that allow chromosomes to be accurately identified in a karyotype.
• There are several other stains that can be used in a similar manner.
• Chromosome abnormalities in some cases can be identified visually by looking at the banding pattern, but this technique reveals differences (for instance, larger deletions) only to a resolution of about 4 Mb.
• Smaller abnormalities (microdeletions)

must be identified in other ways (FISH).

The chromosomes depicted in the figure have been stained with Giemsa.

Chromosome nomenclature

Common Symbols Used in Karyotype Nomenclature

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Chromosome nomenclature

One of the characteristics described is the relative position of the centromere.

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Metacentric chromosomes: have the centromere near the middle.

Submetacentric chromosomes have the centromere displaced toward one end. The p and q arms are evident.

Acrocentric chromosomes have the centromere far toward one end. The p arm contains little genetic information, most of it residing on the q arm.

Only the acrocentric chromosomes are

involved in Robertsonian translocations.

Numerical chromosome abnormalities

Euploidy

Euploid Cells (multiple of 23 chromosomes)

• Haploid are euploid cells that have 23 chromosomes (one member of each pair): gametes (sperm and egg cells)

• Diploid (46 chromosomes or both members of each pair): most somatic cells

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Two types of euploid cells with abnormal numbers of chromosomes (rare lethal condition) are seen in humans:

• Triploid (69 chromosomes or 3 copies of each chromosome)
• Tetraploid (92 chromosomes or 4 copies of each chromosome)

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Numerical chromosome abnormalities

Euploidy

Triploidy, which usually occurs as a result of the fertilization of an ovum by 2 sperm cells, is common at conception, but the vast majority of these conceptions are lost prenatally. However, about 1 in 10,000 live births is a triploid. These babies have multiple defects of the heart and central nervous system, and they do not survive.

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Tetraploidy, this lethal condition is much rarer than triploidy among live births: Only a few cases have been described.

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Numerical chromosome abnormalities

Aneuploidy

Aneuploidy, a deviation from the euploid number, represents the gain (+) or

loss (-) of a specific chromosome.

Two major forms of aneuploidy are observed:

• Monosomy (loss of a chromosome)

• Trisomy (gain of a chromosome)

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• Autosomal aneuploidy

Two generalizations are helpful:

• All autosomal monosomies are inconsistent with a live birth.

• Only 3 autosomal trisomies (trisomy 13, 18, and 21) are consistent with

a live birth.

• Trisomy 21 (47,XY,+21 or 47,XX,+21); Down Syndrome
• Trisomy 18 (47,XY,+18 or 47,XX,+18); Edward Syndrome
• Trisomy 13 (47,XY,+13 or 47,XX,+13); Patau Syndrome

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• Trisomy is the most common genetic cause of spontaneous loss of pregnancy.

Numerical chromosome abnormalities

• Autosomal aneuploidy

Trisomy 21 (47,XY,+21 or 47,XX,+21); Down Syndrome

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• Most common autosomal trisomy

• Mental retardation

• Short stature

• Hypotonia

• Depressed nasal bridge, upslanting palpebral fissures, epicanthal fold

• Congenital heart defects in approximately 40% of cases

• Increased risk of acute lymphoblastic leukemia

• Alzheimer disease by fifth or sixth decade (amyloid precursor protein,

APP gene on chromosome 21)

• Reduced fertility

• Risk increases with increased maternal age

Numerical chromosome abnormalities

• Autosomal aneuploidy

Trisomy 18 (47,XY,+18 or 47,XX,+18); Edward Syndrome

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• Clenched fist with overlapping fingers

• Inward turning, “rocker-bottom” feet

• Congenital heart defects

• Low-set ears,

micrognathia (small lower jaw)

• Mental retardation

• Very poor prognosis

Numerical chromosome abnormalities

• Autosomal aneuploidy

Trisomy 13 (47,XY,+13 or 47,XX,+13); Patau Syndrome

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• Polydactyly (extra fingers and toes)

• Cleft lip, palate

• Microphthalmia (small eyes)

• Microcephaly, mental retardation

• Cardiac and renal defects

• Very poor prognosis

Numerical chromosome abnormalities

• Sex chromosome aneuploidy

Aneuploidy involving the sex chromosomes is relatively common and tends to have less severe consequences than does autosomal aneuploidy.

Some generalizations are helpful:

• At least one X chromosome is required for survival.

• If a Y chromosome is present, the phenotype is male (with minor

exceptions).

• If more than one X chromosome is present, all but one will become a Barr body in each cell.

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The two important sex chromosome aneuploidies are

• Turner syndrome and
• Klinefelter syndrome.

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Numerical chromosome abnormalities

• Sex chromosome aneuploidy

Klinefelter Syndrome (47,XXY)

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• Testicular atrophy

• Infertility

• Gynecomastia

• Female distribution of hair

• Low testosterone

• Elevated FSH and LH

• High-pitched voice

Numerical chromosome abnormalities

• Sex chromosome aneuploidy

Turner Syndrome (45,X or 45,XO)

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• Only monosomy consistent with life

• 50% are 45,X

• Majority of others are mosaics for 45,X and one other cell lineage

(46,XX, 47,XXX, 46,XY)

• Females with 45,X;46,XY are at increased risk for gonadal blastoma.

• Short stature

• Edema of wrists and ankles in newborn

• Cystic hygroma in utero resulting in excess nuchal skin and “webbed” neck

• Primary amenorrhea

• Coarctation of the aorta or other congenital heart defect in some cases

• Infertility

• Gonadal dysgenesis

Nondisjunction is the usual cause of aneuploidies

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Disjunction During Normal Meiosis

Nondisjunction is the usual cause of aneuploidies

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Nondisjunction During Meiosis 1

Nondisjunction is the usual cause of aneuploidies

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Nondisjunction During Meiosis 2

Nondisjunction is the usual cause of aneuploidies

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• Nondisjunction is the usual cause of aneuploidies including Down,

Edward, Patau, Turner, and Klinefelter syndromes.

• Nondisjunction is more likely to occur during oogenesis than during

spermatogenesis.

• Nondisjunction is more likely with increasing maternal age.

Environmental agents (e.g., radiation, alcohol) appear to have no measurable influence.

• Nondisjunction is more likely in meiosis I than meiosis II.

Clinical Correlate: Maternal Age and Risk of Down Syndrome

Surveys of babies with trisomy 21 show that 90–95% of the time, the extra copy of the chromosome is contributed by the mother (similar figures are obtained for trisomies of the 18th and 13th chromosomes).

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The increased risk of Down syndrome with maternal age is well documented.

• For women age <30 the risk of bearing a child with Down is <1/1,000.

• At age 35 the risk increases to about 1/400.

• At age 40 the risk increases to 1/100.

• At age ≥45 the risk increases to about 1/25.

Nondisjunction is the usual cause of aneuploidies

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Clinical Correlate: Maternal Age and Risk of Down Syndrome

• This increase reflects an elevated rate of nondisjunction in older ova (recall that all of a woman’s egg cells are formed during her fetal development and they remain suspended in prophase I until ovulation).
• There is no corresponding increase in risk with advanced paternal age; sperm cells are generated continuously throughout the life of the male.
• The increased risk of trisomy with advanced maternal age motivates >50% of pregnant women in North America to undergo prenatal diagnosis (typically amniocentesis or chorionic villus sampling).
• Down syndrome can also be screened by assaying maternal serum levels of
• α-fetoprotein,
• Chorionic gonadotropin, and
• Unconjugated estriol.

This so-called triple screen can detect approximately 70% of fetuses with Down.

Structural chromosome abnormalities

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• Structural alterations of chromosomes occur when chromosomes are broken by agents termed clastogens (e.g., radiation, some viruses, and some chemicals).
• Some alterations may result in a loss or gain of genetic material and are called unbalanced alterations;
• balanced alterations do not result in a gain or loss of genetic material and usually have fewer clinical consequences.
• As with other types of mutations, structural alterations can occur either in the germ line or in somatic cells. The former can be transmitted to offspring. The latter, although not transmitted to offspring, can alter genetic material such that the cell can give rise to cancer.

Structural chromosome abnormalities

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• Translocations
• Translocations occur when chromosomes are broken and the broken elements reattach to other chromosomes.
• Translocations can be classified into two major types:

reciprocal and Robertsonian.

• Reciprocal translocation

Reciprocal translocations occur when genetic material is exchanged between nonhomologous chromosomes; for example, chromosomes 2 and 8. If this happens during gametogenesis, the offspring will carry the reciprocal translocation in all his or her cells and will be called a translocation carrier.

The karyotype would be 46,XY,t(2p;8p) or 46,XX,t(2p;8p). Because this individual has all of the genetic material (balanced, albeit some of it misplaced because of the translocation), there are often no clinical consequences other than during reproduction.

A Reciprocal Translocation

Structural chromosome abnormalities

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• Reciprocal translocation
• In a translocation carrier, during gametogenesis and meiosis, unbalanced genetic material can be transmitted to the offspring, causing partial trisomies and partial monosomies typically resulting in pregnancy loss.

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• During meiosis 1, the translocated chromosomes may segregate as chromosome 8 or as chromosome 2, producing a variety of possible gametes with respect to these chromosomes.
• For example, see the following figure, which depicts a man who is a translocation carrier mating with a normal woman. The diagram in the upper right is used to depict the possible sperm the father can produce.
• It acknowledges that the translocated chromosomes can potentially pair with either of the two homologs (2 or 8) during meiosis.

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Consequences of a Reciprocal Translocation (Illustrated with Male)

Alternate and adjacent segregation are diagrams used to predict the possible gametes

produced by a translocation carrier.

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• Adjacent segregation: chromosomes from adjacent quadrants (next to each other) enter a gamete

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• Alternate segregation: chromosomes from alternate (diagonally opposed)

quadrants enter a gamete

Structural chromosome abnormalities

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• Reciprocal translocation
• Sperm that contain balanced chromosomal material (labeled alternate segregation in the diagram) produce either
• a normal diploid conception or
• another translocation carrier.
• Both are likely to be live births.

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• Sperm that contain unbalanced chromosomal material (labeled adjacent segregation in the diagram) produce conceptions that have partial monosomies and partial trisomies.
• These conceptions are likely to result in pregnancy loss.

Structural chromosome abnormalities

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• Reciprocal Translocations After Birth.
• Reciprocal translocations may occur by chance at the somatic cell level throughout life.

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• Because these translocations involve only a single cell and the genetic material is balanced, there is often no consequence.
• Rarely, however, a reciprocal translocation may alter the expression or structure of an oncogene or a tumor suppressor gene, conferring an abnormal growth advantage to the cell.

Chronic Myelogenous Leukemia and the Philadelphia Chromosome

Rearrangements in somatic cells can lead to the formation of cancers by

altering the genetic control of cellular proliferation.

A classic example is a reciprocal translocation of the long arms of chromosomes 9 and 22, termed the Philadelphia chromosome.

This translocation alters the activity of the abl proto-oncogene (proto-oncogenes can lead to cancer).

When this alteration occurs in hematopoietic cells, it can result in chronic myelogenous leukemia.

Structural chromosome abnormalities

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• Reciprocal Translocations After Birth.
• More than 100 different chromosome rearrangements involving nearly every chromosome have been observed in more than 40 types of cancer.

• Translocations Involving Oncogenes

Translocations are seen in a variety of cancers.

• t(9;22) chronic myelogenous leukemia (c-abl)

• t(15;17) acute myelogenous leukemia (retinoid receptor-α)

• t(14;18) follicular lymphomas (bcl-2 that inhibits apoptosis)

• t(8;14) Burkitt lymphoma (c-myc)

• t(11;14) mantle cell lymphoma (cyclin D)

Translocation between chromosome 9 and 22.The altered chr. 22 is the “Philadelphia chromosome”.

Structural chromosome abnormalities

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• Robertsonian translocations
• These translocations are much more common than reciprocal translocations and are estimated to occur in approximately 1 in 1,000 live births.
• They occur only in the acrocentric chromosomes (13, 14, 15, 21, and 22) and involve the loss of the short arms of two of the chromosomes and subsequent fusion of the long arms.

• An example of a Robertsonian translocation involving chromosomes 14 and 21 is shown in the Figure.
• The karyotype of this (male) translocation carrier is designated 45,XY,–14,–21,+t(14q;21q).
• Because the short arms of the acrocentric chromosomes contain no essential genetic material, their loss produces no clinical consequences, and the translocation carrier is not clinically affected.

A Robertsonian Translocation

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Consequences of a Robertsonian Translocaton

in One Parent (Illustrated with Male)

Structural chromosome abnormalities

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• Robertsonian translocations
• When the carrier’s germ cells are formed through meiosis, the translocated chromosome must pair with its homologs.
• If alternate segregation occurs, the offspring will inherit either
• a normal chromosome complement or
• will be a normal carrier like the parent.
• If adjacent segregation occurs, the offspring will have an unbalanced chromosome complement
• an extra copy (trisomy) or
• missing copy (monosomy) of the long arm of chromosome 21 or 14).
• Because only the long arms of these chromosomes contain genetically important material, the effect is equivalent to a trisomy or monosomy.

Structural chromosome abnormalities

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• Robertsonian Translocation and Down Syndrome.
• Approximately 5% of Down syndrome cases are the result of a Robertsonian translocation affecting chromosome 14 and chromosome 21.
• When a translocation carrier produces gametes, the translocation chromosome can segregate with the normal 14 or with the normal 21.
• Although adjacent segregation usually results in pregnancy loss, one important exception is that which produces trisomy 21. This may be a live birth, resulting in an infant with Down syndrome.
• One can determine the mechanism leading to Down syndrome by examining the karyotype.
• Trisomy 21 due to nondisjunction during meiosis (95% of Down syndrome cases),
• the karyotype: 47,XX,+21 or 47,XY.+21.
• In the 5% of cases where Down syndrome is due to a Robertsonian translocation in a parent,
• the karyotype: 46,XX,-14,+t(14;21), or 46,XY,-14,+t(14;21).
• The key difference is 47 versus 46 chromosomes in the individual with Down syndrome.

Structural chromosome abnormalities

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• Robertsonian Translocation and Down Syndrome.

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• The reason for the difference of the recurrence risk between males and females (translocation carriers) is not well understood.
• The elevated recurrence risk for translocation carriers versus noncarriers underscores the importance of ordering a chromosome study when Down syndrome is suspected in a newborn.

Structural chromosome abnormalities

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• Deletions

• A deletion occurs when a chromosome loses some of its genetic information.
• Terminal deletions (the end of the chromosome is lost) and

interstitial deletions (material within the chromosome is lost) may be caused by agents that cause chromosome breaks and by unequal crossover during meiosis.

• Deletions can be large and microscopically visible in a stained preparation.

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The figure below shows both an

interstitial deletion and a terminal

deletion of 5p.

Both result in Cri-du-chat syndrome.

• 46,XX or 46,XY, del(5p)

• High-pitched, cat-like cry

• Mental retardation, microcephaly

• Congenital heart disease

Structural chromosome abnormalities

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• Microdeletions

• Some deletions may be so small that they are not readily apparent microscopically without special fluorescent probes (FISH).
• Examples include Prader-Willi and Angelman syndromes.
• If a microdeletion includes several contiguous genes, a variety of phenotypic outcomes may be part of the genetic syndrome.

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• Examples include:

• DiGeorge syndrome: congenital absence of the thymus and parathyroids,

hypocalcemic tetany, T-cell immunodeficiency, characteristic facies with cleft palate, heart defects.

• Wilms tumor: aniridia, genital abnormalities, mental retardation (WAGR)

• Williams syndrome: hypercalcemia, supravalvular aortic stenosis, mental retardation, characteristic facies

Other chromosome abnormalities

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• Structural Abnormalities

• Translocations (Robertsonian and reciprocal)

• Deletions and duplications

• Inversions (pericentric and paracentric)

• Ring chromosomes

• Isochromosomes

Their frequency and clinical consequences tend to be less severe than those of translocations and deletions.

• Inversions
• Inversions occur when the chromosome segment between two breaks is reinserted in the same location but in reverse order.

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• Inversions that include the centromere are termed pericentric, whereas those that do not include the centromere are termed paracentric.

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• The karyotype of the pericentric inversion shown in the following figure, extending from 3p21 to 3q13 is 46,XY,inv(3)(p21;q13).

Other chromosome abnormalities

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• Inversions
• Inversion carriers still retain all of their genetic material, so they are usually unaffected (although an inversion may interrupt or otherwise affect a specific gene and thus cause disease).
• Because homologous chromosomes must line up during meiosis, inverted chromosomes will form loops that, through recombination, may result in a gamete that contains a deletion or a duplication, which may then be transmitted to the offspring.

Pericentric Inversion of Chromosome 16

A male infant, the product of a full-term pregnancy, was born with

hypospadias and ambiguous genitalia. He had a poor sucking reflex, fed

poorly, and had slow weight gain. He had wide-set eyes, a depressed nasal

bridge, and microcephaly. The father stated that several members of his

family, including his brother, had an abnormal chromosome 16. His brother

had two children, both healthy, and the father assumed that he would also

have normal children. Karyotype analysis confirmed that the father had a

pericentric inversion of chromosome 16 and that his infant son had a

duplication of material on 16q, causing a small partial trisomy.

Other chromosome abnormalities

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• Ring Chromosome
• A ring chromosome can form when a deletion occurs on both tips of a chromosome and the remaining chromosome ends fuse together.
• The karyotype for a female with a ring chromosome X would be 46,X,r(X).
• Ring chromosomes are often lost, resulting in a monosomy (e.g., loss of a ring X chromosome would produce Turner syndrome).
• These chromosomes have been observed

at least once for each human chromosome.

Ring X-Chromosome

Other chromosome abnormalities

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• Isochromosome
• When a chromosome divides along the axis perpendicular to its normal axis of division, an isochromosome is created (i.e., 2 copies of one arm but no copy of the other).
• Because of the lethality of autosomal isochromosomes, most isochromosomes that have been observed in live births involve the X chromosome, as shown in the following figure.
• The karyotype of an isochromosome for the

long arm of the X chromosome would be

46,X,i(Xq); this karyotype results in an

individual with Turner syndrome, indicating

that most of the critical genes responsible

for the Turner phenotype are on Xp.

Isochromosome X

Advances in molecular cytogenetics

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Although chromosome abnormalities are still commonly visualized by examining

metaphase chromosomes under a microscope, several powerful new techniques

combine cytogenetics with modern molecular methods.

• Two of the most important techniques are:
• Fluorescence in situ Hybridization (FISH)
• Spectral Karyotyping

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• Fluorescence in situ Hybridization (FISH)

• In fluorescence in situ hybridization (FISH), a chromosome-specific DNA segment is labeled with a fluorescent tag to create a probe.
• This probe is then hybridized with the patient’s chromosomes, which are visualized under a fluorescence microscope.
• Because the probe will hybridize only with a complementary DNA sequence, the probe will mark the presence of the chromosome segment being tested.
• For example, a probe that is specific for chromosome 21 will hybridize in 3 places in the cells of a trisomy 21 patient, providing a diagnosis of Down syndrome.

A normal diploid cell with 2 signals for chr. 21

A trisomic cell with 3 signals for chr. 21

Advances in molecular cytogenetics

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• Fluorescence in situ Hybridization (FISH)

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• FISH is also commonly used to detect deletions.
• An analysis using a probe that hybridizes to the region of 15q corresponding to Prader-Willi syndrome will show only a single signal in a patient, confirming the diagnosis of this deletion syndrome.
• An advantage of FISH is that chromosomes do not have to be in the metaphase stage for accurate diagnosis.
• Even though interphase and prophase chromosomes cannot be clearly visualized themselves, the number of hybridization signals can still be counted accurately.
• FISH analysis detects:
• Aneuploidies,
• Translocations, and
• Deletions (including microdeletions).

Advances in molecular cytogenetics

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• Spectral Karyotyping
• Spectral karyotyping involves the use of 5 different fluorescent probes that hybridize differentially to different sets of chromosomes.
• In combination with a special camera and image-processing software, this technique produces a karyotype in which every chromosome is “painted” a different color.

• This allows for the ready visualization of chromosome rearrangements such as small translocations, e.g., the Philadelphia chromosome rearrangement t(9;22) involved in chronic myelogenous leukemia.

Spectral Karyotyping

Chapter 3: Cytogenetics

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• Review Questions

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• Select the ONE best answer.

1. A 26-year-old woman has produced two children with Down syndrome,

and she has also had two miscarriages. Which of the following would be

the best explanation?

A. Her first cousin has Down syndrome.

B. Her husband is 62 years old.

C. She carries a reciprocal translocation involving chromosomes 14 and 18.

D. She carries a Robertsonian translocation involving chromosomes 14 and 21.

E. She was exposed to multiple x-rays as a child.

Chapter 3: Cytogenetics

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• Review Questions

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• Select the ONE best answer.

2. A 6-year-old boy has a family history of mental retardation and has developmental delay and some unusual facial features. He is being evaluated

for possible fragile X syndrome. Which of the following would be most

useful in helping establish the diagnosis?

A. Genetic test for a trinucleotide repeat expansion in the fragile X gene

B. IQ test

C. Karyotype of the child’s chromosomes

D. Karyotype of the father’s chromosomes

E. Measurement of testicular volume

Chapter 3: Cytogenetics

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• Review Questions

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• Select the ONE best answer.

3. A couple has one son, who is age 7. Multiple attempts to have a second

child have ended in miscarriages and spontaneous abortions. Karyotypes

of the mother, the father, and the most recently aborted fetus are represented schematically below. What is the most likely explanation for the

most recent pregnancy loss?

A. Aneuploidy in the fetus

B. Fetus identified as a reciprocal translocation carrier

C. Nondisjunction during oogenesis in the mother

D. Partial monosomy and trisomy in the fetus

E. Unbalanced chromosomal material in the father

Chapter 3: Cytogenetics

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• Review Questions

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• Select the ONE best answer.

4. A woman brings her 16-year-old daughter to a physician because she has not yet begun menstruating. Although her parents are both 1.75 meters, the patient is 1.5 meters and has always been below the 50th percentile in height. Physical examination reveals no breast development.

She has no problems in school and is of normal intelligence.

What is the most likely underlying basis for her condition?

A. A 45,X karyotype

B. A balanced reciprocal translocation

C. A balanced Robertsonian translocation

D. Two Barr bodies

E. Deletion of an imprinted locus

Chapter 3: Cytogenetics

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• Review Questions

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• Select the ONE best answer.

5. A 38-year-old woman in her 15th week of pregnancy undergoes ultrasonography that reveals an increased area of nuchal transparency.

Amniocentesis is recommended and performed at 16 weeks’ gestation.

The amniotic karyotype is 46,XYadd(18)(p.11.2), indicating additional

chromosomal material on the short arm of one chromosome 18 at band

11.2. All other chromosomes are normal.

What is the most likely cause of this fetal karyotype?

A. A balanced reciprocal translocation in one of the parents

B. A balanced Robertsonian translocation in one of the parents

C. An isochromosome 18i(p) in one of the parents

D. Nondisjunction during meiosis 1 in one of the parents

E. Nondisjunction during meiosis 2 in one of the parents

Chapter 3: Cytogenetics

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• Review Questions

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• Select the ONE best answer.

6. A 37-year-old woman is brought to emergency department because of

crampy abdominal pain and vaginal bleeding for 3 hours. She is 11 weeks

pregnant. This is her first pregnancy. Her pregnancy has been unremarkable until this episode. Her temperature is 36.8 C (98.2 F), pulse is 106/min, blood pressure is 125/70 mm Hg, and respiration rate is 22/min. Speculum examination shows the presence of blood in the vagina and cervical dilatation. Inevitable spontaneous abortion is suspected. After discussing the condition with the patient, she gave her consent for dilatation and curettage. What is the most common cause of spontaneous abortions?

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A. Chromosomal abnormality, polyploidy

B. Chromosomal abnormality, monosomy X

C. Chromosomal abnormality, trisomy

D. Effects of environmental chemicals

E. Immunologic rejection

F. Infection

G. Maternal endocrinopathies

H. Physical stresses

I. Teratogenic drugs