Abnormalities of Chromosome Number

Question 1

What are the two major categories of chromosome abnormalities?

Answer 1

numerical and structural

Question 2

Considering all numerical and structural abnormalities, an infinite number of errors are possible according to scientific principles, but most of these are never observed clinically. Why could that be so?

Answer 2

(1) The error may be “mild” with no discernable effect on phenotype (nothing to diagnose).
(2) Or the other extreme, the error is so severe that it is lethal (There is selection against the abnormal cell line or embryo; the abnormal cell line dies out, or the embryo/fetus miscarries.) An abnormality that doesn’t persist has little chance to be observed and is very unlikely to be diagnosed.
(3) It also is possible for an abnormal phenotype to be present, yet never come to clinical attention (Phenotype may be at the mild end of the spectrum, or the individual remains undiagnosed, in spite of being affected. Certainly, many conditions are underdiagnosed.)


Question 3

What is error in cell division whereby improper segregation leads to abnormal chromosome number (monosomy or trisomy) called?

Answer 3

nondisjunction

Question 4

Increased risk of nondisjunction during meiosis I is associated with what?

Answer 4

increased maternal age

Question 5

What is polyploidy?

Answer 5

an abnormality involving complete sets of chromosomes.

In triploidy, there are three copies of EACH chromosome, and in tetraploidy, there are four copies of each chromosome.

Question 6

Would someone who is polyploid be considered euploid or aneuploid?

Answer 6

euploid

Question 7

What does euploid mean?

Answer 7

A euploid cell has one or more complete sets of chromosomes. In humans one normal set has 23 chromosomes.

The terms used to describe normal chromosome number are haploid (for a gamete) and diploid (for a somatic cell).

Question 8

What are some examples of aneuploidy?

Answer 8

monosomy (loss of one chromosome) and trisomy (gain of one chromosome).

Question 9

What is ISCN?

Answer 9

International System for Human Cytogenetic Nomenclature.

ISCN is the professional group that sets standards and guidelines for the technical description of chromosome abnormalities, thus serving the important function of providing a standard language.

Question 10

How would “45,X/46,XX” be interpreted on a very basic level? What is it describing?

Answer 10

mosaicism (Turner’s to be specific). The “/” separates two different cell lines

Question 11

Can nondisjunction happen on any chromosome? If not, which ones can it occur on?

Answer 11

It can occur on ALL chromosomes.

Although monosomy or trisomy can arise for any chromosome, most are never seen clinically.

Question 12

What are the three viable autosomal trisomies?

Answer 12

13, 18, 21. All other autosomal aneuploidies are gestational lethals

Question 13

Are sex chromosome aneuploidies generally more or less severe than autosomal aneuploidies?

Answer 13

They are generally less of a problem. This makes sense, given normal differences in sex chromosome complement between males and females. After all, half the species gets along fine with no Y chromosome, and the other half manages pretty well with a single X chromosome. However, there are obligatory genes on the X chromosome, and at least one copy of the X chromosome is required.

Question 14

How is aneuploidy complicated (or moderated in some cases) by mosaicism?

Answer 14

When mitotic nondisjunction gives rise to multiple cell lines, most often there is a mixture of varying proportions of abnormal and normal cells. The normal cell line will tend to moderate the abnormal phenotype associated with the aneuploid cells. For example, someone with mosaic trisomy 21 (normal cells in addition to trisomy 21 cells) will have a less severe Down syndrome phenotype. An abnormality that would be lethal on its own (for example, trisomy 22) can be viable when present as mosaicism. A person with mosaic trisomy 22 might have an abnormal phenotype characterized by delayed growth, intellectual disability, and minor physical anomalies.

Question 15

Which autosomal monosomies are viable?

Answer 15

NONE. they are all gestational lethal

Question 16

Which show higher incidences of aneuploidy, sperm or oocytes?

Answer 16

oocytes (~20%) vs. sperm (1-2%)

Question 17

Are chromosome abnormalities a major cause of miscarriage?

Answer 17

Yes. Roughly 35% of pregnancies that end prior to 20 weeks will be chromosomally abnormal. Thus, importantly, unavoidable, random errors of meiosis are a major cause of miscarriage.

Question 18

What is the significance of the fact that chromosome abnormalities occurring during the first 20 weeks (and often lead to spontaneous abortion) is much higher (35%) than those children who are stillbirths due to chromosome abnormality (4%) and those who have viable chromosome abnormalities (0.3%)?

Answer 18

chromosomally abnormal conceptions tend to be weeded out early in gestation. Even the viable aneuploidies are associated with a significant loss rate.

the take home message is that human development is quite intolerant of chromosome imbalance.

Question 19

T or F. The earlier the spontaneous abortion, the higher the incidence of chromosome abnormality

Answer 19

T.

~50% of miscarriages are chromosomally abnormal, with incidence as high as 90% in very early pregnancy

~95% of all chromosomally abnormal pregnancies are lost prior to term

Other causes of SAb include non-genetic congenital anomalies & host factors.

Question 20

What is the most common chromosome abnormality observed in spontaneous abortions?

Answer 20

45, X (~20%)

NOTE: all cases of trisomy together total to 54% and together comprise the most common source of spontaneous abortion. However, alone the highest occurrence of SA caused by trisomy is trisomy 16 (16%), so 45,X is slightly more common

Question 21

If you observed a pregnancy that lasted until last in the second trimester/early third and suspected trisomy as the cause of the subsequent spontaneous abortion that occurred, what chromosomes might you suspect?

Answer 21

16 and 22. For some reason, the genes on chromosome 16 (and to a much lesser extent, on chromosome 22) enable significant gestational survival for trisomy 16 (and trisomy 22). Yet, these pregnancies absolutely never survive to term

Note that trisomy 18 and 21 are well represented in spontaneous abortuses, yet some of these will survive to term.

Question 22

Are autosomal monosomies a common cause of SA?

Answer 22

No. They account for roughly 1% of SA.

Question 23

Which is most common: trisomy 21, 18, or 13

Answer 23

21, then 18, then 13

Question 24

What is polyploidy?

Answer 24

the presence of extra full sets of chromosomes

Question 25

What is triploidy most commonly caused by?

Answer 25

Most often caused by fertilization by two sperm (dispermy)

Common at conception & common cause of spontaneous abortion (miscarriage).

Question 26

How would tetraploidy arise?

Answer 26

Tetraploidy is very rare, and, when it occurs, the most common cause is mitotic failure in early development. For example, a conceptus with the normal chromosome number of 46 might replicate its chromosomes but then fail to complete mitosis. This scenario would double the chromosome number. Subsequent “normal” cleavage divisions would generate cells where each one contains 92 chromosomes.

Question 27

Is polyploidy ever compatible with life?

Answer 27

No, never

Question 28

When does triploidy typically result in SA? I.e. what part during gestation

Answer 28

Very early during a pregnancy, However, some (rare) cases of triploidy can survive until late into the pregnancy and even result in a birth taking place. However, remember that a triploidy affected individual has ZERO chance of survival outside the womb

Question 29

What is the shorthand for Down Syndrome?

Answer 29

47, XY, +21

Question 30

Can Down Syndrome arise from mosaicism? If so, how is the disease affected by the presence of mosaicism?

Answer 30

Yes. Patients with mosaicism may have a milder phenotype. For example, their intellectual disability may be less severe, and they may be at the high-functioning end of the expected range

Most often, mosaic patients started out at conception as trisomy 21, and then one cell lost the extra 21 early in development, giving rise to a second, normal cell line. ( it could also happen the other way around.)

Question 31

Besides nondisjunction (which occurs for ~95% of down syndrome cases), what else can cause down syndrome?

Answer 31

“Translocation Down syndrome”. These individuals have three copies of all the genes on the long arm of chromosome 21 and a typical Down syndrome phenotype, but the extra genetic material is part of a structurally abnormal chromosome called a Robertsonian translocation.

An important clinical distinction is that translocation Down syndrome often is inherited. Accurate diagnosis is necessary for accurate assessment of recurrence risk.

Question 32

How common is Trisomy 21?

Answer 32

1 in 800 births. (It’s significantly more common than that at conception but is associated with significant prenatal lethality)

Question 33

Trisomy 18 is aka?

Answer 33

Edward’s syndrome

all cases are caused my maternal nondisjunction

Question 34

What are some clinical manifestations of Trisomy 18?

Answer 34

Severe mental retardation
Prenatal growth deficiency
Congenital heart defect
Rocker bottom feet
Clenched hand
Other anomalies
Life expectancy

Question 35

How common is Trisomy 18?

Answer 35

It is observed in 1 in 6000 births. It is significantly more common than that at conception but is associated with very high prenatal lethality similar to Trisomy 21

Question 36

Trisomy 13 is aka?

Answer 36

Patau syndrome

Question 37

What is a plausible reason for why trisomy 13 is the most severe of the viable trisomies?

Answer 37

Chromosome 13 is the largest chromosome of the three and thus has the greatest phenotypic effect

However, do keep in mind that viability is not simply a matter of chromosome size. Other similarly sized chromosomes [14, 15, 16, 17, 19, 20, 22] are nonviable in the trisomic state.

Presumably, the genes contained on each chromosome factor into survival potential.

Question 38

What is trisomy 13 caused by?

Answer 38

The majority of trisomy 13 cases result from nondisjunction, and risk increases with maternal age. Like trisomy 21, a minority of cases (in this disorder, less than 20%) are caused by a Robertsonian translocation involving chromosome

Question 39

What is the outlook for individuals with trisomy 13?

Answer 39

very poor

Question 40

What is the incidence of all sex chromosome abnormalities?

Answer 40

1 in 500

Question 41

Monosomy X is aka?

Answer 41

Turner syndrome

Question 42

What are some clinical manifestations of Turner’s Syndrome?

Answer 42

Prenatal: cystic hygroma (lymphatic malformation involving the neck)

Newborn lymphedema (swelling of hands & feet)

Webbing of neck

Short stature

Ovarian dysgenesis (streak ovaries); primary amenorrhea

Heart defect (e.g. coarctation of the aorta)

Normal intelligence

Ovaries do not develop normally, leading to delayed sexual maturation, absence of secondary sexual characteristic, and lack of fertility.

Question 43

What are the causes of Turner syndrome?

Answer 43

50% 45,X (meiotic nondisjunction, 80% of which is paternal)

35% mosaic 45,X/46,XX (or 45,X/47,XXX or 45,X/46,X,i(Xq) etc.)

5% mosaic with a Y-bearing cell line (45,X/46,XY or 45,X/46,X,i(Yq) etc.)

10% structural abnormalities of X chromosome (46,X,i(Xq) etc.)

Question 44

Is autosomal nondisjunction more likely to have a maternal or paternal cause?

Answer 44

maternal

Question 45

Is sex chromosome nondisjunction more likely to have a maternal or paternal cause? Why?

Answer 45

paternal. Because of the challenges associated with correctly fairly the different X and Y chromosomes up and ensuring proper operation during meiosis

Question 46

Is mosaicism common in patient’s with Turner’s syndrome? How does mosaicism affect the severity of the disease?

Answer 46

More than one third of Turner syndrome individuals have mosaicism. They have one cell line with monosomy X plus a second cell line that is chromosomally normal (or more rarely, the second cell line may exhibit some other abnormality).

Consistent with general principles of mosaicism, mosaic Turner syndrome individuals are expected to be more mildly affected

Question 47

What is an i(Xq) chromosome?

Answer 47

aka isochromosome X

chromosome has two X long arms joined by a single centromere and NO copy of Xp

this category of patients has one normal copy of X and, therefore, only one copy of Xp (aka monosomy Xp)

monosomy X is sufficient to cause Turner’s

Question 48

Does the risk of Turner’s increased with associated increase in maternal age?

Answer 48

No, because the vast majority of cases are associated with paternal nondisjunction

Question 49

Paradoxes of Turner Syndrome

Answer 49

In spite of the relatively mild clinical phenotype, the fetal loss rate for Turner syndrome is astronomically high. Monosomy X is very common at conception and is frequently observed in spontaneous abortuses, but there is less than 1% chance that a Turner syndrome conception will make it to term. If you reflect back on the numbers provided for the autosomal trisomies, there was a positive correlation between fetal loss rate and severity of the syndrome. Here, we see the opposite (high loss rate; mild phenotype). One possible explanation that has been proposed is that mosaicism improves the survival potential.

Question 50

What is Klinefelter Syndrome?

Answer 50

Disease where males carry an extra X chromosome (47, XXY)

Question 51

What are the typical clinical manifestations of Klinefelter Syndrome?

Answer 51

Tall with long extremities
Primary hypogonadism
Gynecomastia (breast development)
Reduced IQ (10-15 points)

Question 52

What is the etiology of Klinefelter?

Answer 52

50% paternal nondisjunction (XY)

50% maternal nondisjunction (maternal age effect)

Question 53

Incidence risk of Klinefelter

Answer 53

1 in 1000 male live births
~1/2 spontaneously aborted (this is a very significant prenatal loss rate, in spite of the fact that those who survive have a mild course with no particular postnatal survival risks.)

Question 54

Notes on Triple X syndrome

Answer 54

(47, XXX)

Etiology: 90% maternal nondisjunction with age effect

Essentially normal phenotype; mild learning problems; majority remain undiagnosed

Question 55

Notes on 47, XYY

Answer 55

Incidence ~1 in 1000 male live births

Etiology: paternal meiosis II nondisjunction (no age effect)

Essentially normal phenotype; tall; some risk for educational & behavioral problems