Term
| Numerical chromosomal changes |
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Definition
A gain or loss of the number of chromosomes. For example:
- Euploidy (N, 2N, 3N, 4N)
- Aneuploidy (monosomy, trisomy) |
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Term
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Definition
Exact multiples of one complete chromosome complement. For example:
- N = Haploid 23 chromosomes
- 2N = Diploid 46 chromosomes
23 pairs
- 3N = Triploid 69 chromosomes
- 4N = Tetraploid 92 chromosomes |
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Term
| How many unique chromosomes exist in a diploid human? |
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Definition
| 24 (22 unique autosomes and 2 unique sex chromosomes) |
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Term
| What events might lead to triploidy? |
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Definition
Triploidy may be due to the failure in gametogenesis of one of the meiotic
divisions giving rise to a 2N gamete which, when fertilized by a haploid gamete from the other parent, produces a triploid zygote. Alternatively, a 3N complement may be derived from dispermy, the fertilization of a haploid egg by two sperm, and this generally results in a partial
hydatidiform mole. |
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Term
| What events might lead to tetrapolidy? |
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Definition
| Tetraploidy, on the other hand, is usually a post meiotic event and presents as a duplication of a diploid complement (XXXX or XXYY) most likely due to failure of an early mitotic cleavage division in the zygote. |
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Term
| Are triploidy and tetraploidy compatible with human life? |
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Definition
| No, and affected fetuses will be spontaneously aborted. |
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Term
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Definition
Gain or loss of chromosomes equaling
less than one complete complement. For example:
- Trisomy: 2N + 1 = 47 (Trisomy 13: 47,XX,+13)
- Monosomy: 2N - 1 = 45 (Monosomy 8: 45,XY,-8) |
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Term
| Are most aneuploidies compatible with life? |
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Definition
No, the imbalance of genetic information often leads to spontaneous abortion of the fetus. There are however some exceptions:
- Monosomy of the X chromosome (45X: Turner Syndrome).
- Trisomy 13 (Patau Syndrome)
- Trisomy 18 (Edwards Syndrome)
- Trisomy 21 (Down Syndrome) |
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Term
| T or F: Aneuploidies are almost always inherited. |
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Definition
| False. Aneuploidies are most often due to meiotic or mitotic nondisjunction errors. |
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Term
| Meiotic nondisjunction leading to trisomy (image). |
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Definition
[image]
Aneuploidy may result from a nondisjunction error in either mitosis or meiosis. If a meiotic
error produces a gamete with two copies of an A chromosome (A1 and A2), fertilization with a
normal gamete (A5) will result in
trisomy for the A chromosome. |
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Term
| Which trisomies are viable? |
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Definition
- Trisomy 13 (Patau Syndrome)
- Trisomy 18 (Edwards Syndrome)
- Trisomy 21 (Down Syndrome) |
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
| What are some of the defects associated with Down syndrome? |
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Definition
| Down syndrome occurs in approximately 1 in 700 births. Characteristics include short stature, low set ears, microcephaly, mental retardation, up slanting eyes, short hands, eye folds, protruding tongue, usually infertile. System defects include heart, lung, brain, endocrine system (infertility), susceptibility to infectious disease (15X), increased risk of leukemia (10X), and high frequency of Alzheimer disease. |
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Term
| What is the incidence of Down syndrome? |
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Definition
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Term
| Down syndrome critical region |
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Definition
| A region of chromosome 21 encompassing bands 21q22.12 to 21q22.3, where a third copy of this region will result in down syndrome. In other words, it is not necessary for a patient to have three complete copies of chromosome 21; a third copy of this region of the chromosome due to chromosomal rearrangement will also lead to the defect. |
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Term
| What are the three causes of Down syndrome and what percentage of patients have each? |
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Definition
1) Trisomy 21; 47,__,+21 (92.5%).
2) Translocation (4.8%).
3) Mosaics; 46,XX/47,XX,+21(2.7%). |
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Term
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Definition
| Results when some of the cells in the body are normal and other cells have trisomy 21 (46,XX/47,XX,+21). This can occur in one of two ways: a nondisjunction event during an early cell division in a normal embryo leads to a fraction of the cells with trisomy 21; or a Down syndrome embryo undergoes nondisjunction and some of the cells in the embryo revert to the normal chromosomal arrangement. |
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Term
| Mosaic down syndrome beginning with normal diploidy (image) |
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Definition
[image]
If the embryo begins with 46 chromosomes, a mitotic error could give rise to some cells with 3 copies of chromosome 21. The reciprocal product, monosomy 21, would not be viable and would die out, leaving the disomy and trisomy cell lines. |
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Term
| Mosaic down syndrome beginning with trisomy (image) |
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Definition
[image]
If the embryo begins with trisomy 21, a nondisjunction error could result in a disomic cell. Here, the reciprocal product is a tetrasomy which is nonviable. Again, the final complement would be a mosaic with both disomic and trisomic cells. |
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Term
| What are some of the defects associated with Patau syndrome? |
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Definition
| Patau syndrome, or trisomy 13, is often characterized by failure to thrive, cleft lip and palate, rocker bottom feet, polydactyly, “punched-out” scalp, small head, heart defect. Severely affected individuals may have cyclopia (single, centrally placed eye) and a malpositioned nose. Patau syndrome has a birth incidence of 1:4,000 to 1:10,000. |
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Term
| What are some of the defects associated with Edwards syndrome? |
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Definition
| Affects 1 in 8000 live births, characterized by low birth weight, small mouth/jaw, ventricular septal defect, hypoplasia of muscles, prominent occiput, low-set malformed ears, rocker bottom feet, and crossed fingers. |
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Term
| In humans, what is the default gender? |
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Definition
| Female. In the absence of any other signal, a female will develop. |
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Term
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Definition
| Females lack the TDF/SRY, so in the absence of that signal, ovaries will develop followed by differentiation of the Műllerian ducts, which will result in the internal female reproductive organs. At the same time, there will be regression of the Wolffian ducts, which are the precursors for the male internal reproductive organs. |
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Term
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Definition
| In the presence of the TDF/SRY signal, testes develop resulting in inhibition and degeneration of the Műllerian ducts. Androgen is produced and this will stimulate proliferation of the Wolffian ducts. Once the sex of an individual has been determined, gain or loss of the key genes or loss of one of the sex chromosomes is clinically irrelevant. |
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Term
| What accounts for sex determination? |
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Definition
| Sex determination in humans is the result of complex biochemical pathways involving the interaction of proteins produced by genes present on the autosomes, the X, and the Y chromosomes. The protein produced by TDF initiates the male developmental pathway, and although this is important, it is not the only factor that defines sex. It is possible to have a fully functional TDF/SRY and have a female phenotype. Other disorders are known to be associated with mutations in different genes within the pathway and can result in ambiguous genitalia or genotype/phenotype mismatch (phenotypic male with an XX sex chromosome complement or a phenotypic female with an XY complement). |
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Term
| Why are females not at a deficit because they have no Y? |
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Definition
| The genes present on the Y chromosome seem to be primarily involved with male characters, so females will not be negatively impacted by their absence. |
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Term
| Why are males not at a deficit because of only 1 X? |
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Definition
| Males and females have equivalent enzyme production from X-linked genes – because of X inactivation. |
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Term
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Definition
| The idea that one X is inactivated in all the somatic cells of a female’s body. This is supported by special staining of buccal cells that will show a dark spot (the condensed X chromosome), known as a Barr body. |
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Term
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Definition
| The inactive X chromosome in a female somatic cell, rendered inactive in a process called lyonization, in those species (including humans) in which sex is determined by the presence of the Y or W chromosome rather than the diploidy of the X or Z. The Lyon hypothesis states that in cells with multiple X chromosomes, all but one are inactivated during mammalian embryogenesis. This happens early in embryonic development at random in mammals. |
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Term
| How many Barr bodies are present in each human cell? |
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Definition
| The total number of Barr bodies in a cell is equal to the total number of X chromosomes minus 1. Thus, an XX female with have one Barr body, and a male with have none. In a female with 3 X chromosomes, there will be 2 Barr bodies. |
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Term
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Definition
| If a female is heterozygous, then there will be subpopulations of cells within her body. Some cells will express the traits present on the maternal X chromosome and some will express the traits present on the paternal X chromosome. |
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Term
| T or F: In females, X inactivation is random. |
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Definition
| In females, X inactivation should be random. That is, approximately half of the cells express one allele, and the other half express the second allele. There will be some statistical variance from this, and within a population of individuals, you would most likely see a bell curve distribution. However, deletion or damage to one of the X chromosomes can lead to a change in the inactivation patterns. A damaged X may be preferentially inactivated, skewing the distribution such that the alleles on the other X chromosome are always expressed. |
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Term
| Non-random X inactivation |
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Definition
In the female, a damaged X may be preferentially inactivated, skewing the distribution such that the alleles on the other X chromosome are always expressed. Take the example of a female heterozygous carrier for an X-linked disease. If the X chromosome with the normal allele is damaged, it will be preferentially inactivated. Thus, the remaining X is active, but it carries the mutation. Thus, this female will have the same gene expression pattern as a male with only one X chromosome. An example of this is Duchenne muscular dystrophy.
A carrier female could be clinically affected with the disease if the chromosome carrying the normal allele is damaged and inactive in all of her cells. |
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Term
| How does X inactivation occur? |
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Definition
| X inactivation is due to methylation of one of the X chromosomes. There is a locus on the X chromosome known as “XIST” which is the primary X inactivation center. Methylation begins at this point and spreads along the length of the X chromosome. Several sites appear to escape inactivation, most notably the pseudoautosomal region. The process irreversible since the inactive X must be reactivated at meiosis so that all gametes will have an active X. |
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Term
| XIST (X-inactive specific transcript) |
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Definition
| An RNA gene on the X chromosome that acts as major effector of the X inactivation process. |
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Term
| What is the incidence of sex chromosome aneuploidies? |
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Definition
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Term
| What are the four most common sex chromosome aneuploidies? |
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Definition
1) Klinefelter syndrome (47,XXY)
2) XYY male
3) XXX female
4) Turner syndrome (45,X) |
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Term
| Why are sex chromosome aneuploidies generally milder than autosomal aneuploidies? |
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Definition
| The effect of X inactivation and the limited number of genes on the Y chromosome. |
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Term
| What is the cause of sex chromosome aneuploidies? |
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Definition
| Nondisjunction errors during meiosis. |
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Term
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Definition
| Often go undetected throughout life. The birth incidence is relatively high, 1 in 1000, but other than being somewhat taller than average, there are no striking features that would indicate a chromosomal abnormality. Some individuals have generalized learning difficulties and so may be identified by school screening programs. XXX females are also detected in infertility clinics, though the cytogenetic abnormality is not related to the reason for referral, since comprehensive evaluations have shown that these individuals are fully fertile and generally have chromosomally normal children. |
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Term
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Definition
| Often go undetected throughout life. XYY affects 1 in 1000 male live births and is the failure of paternal meiosis. Patients are clinically indistinguishable from 46,XY. Characteristics include tall structure, normal intelligence, and normal fertility. |
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Term
| Klinefelter syndrome (47,XXY) |
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Definition
Affects 1 in 1000 male live births. 50% are due to meiosis I error in father. Patients tend to be tall and thin with relatively long legs, and they may have learning difficulties. The most common reason for referral is post pubertal hypogonadism; female-like breast development; and infertility due to small testicles, hyalinized testicular tubules, and azoospermia.
Infertility is usually due to the hyalinized testicular tubules. Unless detected on a prenatal screen, these individuals may never be identified. However, they
can be diagnosed if they have severe learning disabilities, behavioral problems, or on physical exam reporting small testes. They are also picked up in infertility clinics due to the inability of their partner to conceive. |
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Term
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Definition
Affects approximately 1 in 5000 live female births. The phenotype for this disorder is highly variable.
Most Turner syndrome patients are infertile, but some with an X/XX mosaicism can have children. It has also been shown that if donor egg technologies are used, a Turner syndrome patient will be able to have a normal pregnancy and deliver a normal child. Counseling is therefore a challenge, but the currently belief is that Turner syndrome patients can live happy productive lives. |
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Term
| What are the characteristics of Turner syndrome? |
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Definition
| Affects 1 in 5000 live female births and is characterized by short stature (< 4’11”), webbed neck (in utero cystic hygroma), at birth, edema of the hands and feet; after birth – short hands and fingers, heart and renal anomalies, increased carrying angle of the elbow (cubitus valgus), shield chest, low posterior hairline, usually normal intelligence, though may have learning difficulties, gonadal dysgenesis, primary amenorrhea (no menses), usually infertile (but not always). |
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Term
| Where is the critical region for female differentiation? What happens if that region is missing or inactive? |
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Definition
| The critical region for female differentiation has been narrowed to a region of the short arm of the X just proximal to the centromere. If that region is missing or inactive, an individual with Turner syndrome will result. About half of all Turner syndrome patients have the classic 45,X chromosome complement, which represents the only viable live born monosomy. The single X chromosome is usually maternal in origin, indicating that a paternal meiotic nondisjunction is the most common source of error. In addition to 45,X, more complex karyotypes are also possible. |
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Term
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Definition
Individuals with a 45,X/46,XY mosaicism may have a male or female phenotype.
- Male phenotype: usually okay.
- Female (Turner) phenotype: high probability of a problem (e.g. increased risk of gonadoblastoma [a lethal gonadal tumor])-- recommendation to remove gonads. |
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Term
| What phenotype would be expressed in a 45,X/46,XY mosaic? |
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Definition
| Depending on what cells are most prevalent and active at the time of development, a 45,X/46,XY mosaic can have either a male or female phenotype. In such a mosaic, it is the female patient who has the most risk since she may develop gonadoblastoma. |
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Term
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Definition
| (Often due to congenital adrenal hyperplasia); 1 in 20,000 live births are affected by an XX genotype but a male phenotype. CAH is due to a biochemical imbalance. The defect in CAH is the lack of the enzyme 21-hydroxylase. Without this enzyme, the normal biosynthetic pathway is blocked and androgens accumulate in the body. Excessive levels of male hormones in the female circulation may result in a male-appearing infant despite the female chromosome complement. Furthermore, since androgens are capable of crossing the placenta, a normal female fetus may develop ambiguous genitalia due to exposure from excess hormones from a CAH-affected mother. |
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Term
| What is the cause of congenital adrenal hyperplasia? |
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Definition
| A biochemical imbalance; the defect in CAH is the lack of the enzyme 21-hydroxylase. Without this enzyme, the normal biosynthetic pathway is blocked and androgens accumulate in the body. Excessive levels of male hormones in the female circulation may result in a male-appearing infant despite the female chromosome complement. Furthermore, since androgens are capable of crossing the placenta, a normal female fetus may develop ambiguous genitalia due to exposure from excess hormones from a CAH-affected mother. |
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Term
| What is the cause of an XX genotype with a male phenotype? |
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Definition
| 1 in 20,000 live births causes this error in recombination. The pseudoautosomal region is located on the short arms of the X and Y chromosomes. During male meiosis, these regions pair and recombination may occur. In rare instances, an illegitimate recombination may occur involving the SRY which is just proximal to the boundary of the pseudoautosomal region. This may move the SRY to the end of the X chromosome. In a male with such a balanced translocation, there would be no clinical abnormalities, since the genes are all present, though in alternate locations. However, if this male transmits the rearranged X chromosome to an offspring who has received an X from the mother, the resultant child will have an apparent XX chromosome complement. If the TDF/SRY is fully functional, the male developmental pathway will be triggered, and a male or Klinefelter male phenotype will occur. |
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Term
| What would happen is the Y chromosome is missing the TDF/SRY? |
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Definition
| Male development will not occur and the sex determination will default back to female. Such an individual will also lack two intact copies of the proximal X short arm, and this will prevent “normal” female development. A Turner syndrome individual will most likely result. |
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Term
| Androgen insensitivity (testicular feminization) |
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Definition
| the Y chromosome is intact, and the TDF is present and functional. The problem is a mutation of the androgen receptor gene located on the long arm of the X chromosome (Xq21.3) that results in no androgen receptor protein being produced. The TDF protein will initiate male development, but the pathway will be blocked at the point where the androgen receptor protein is required to form a complex between testosterone and dihydrotestosterone. Without this critical step, further male differentiation is not possible, and the phenotype will default back to female. However, these individuals are infertile due to the lack of any functional internal genitalia and commonly present with a blind vagina and testes in the abdomen or inguinal canal. |
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Term
| What is the problem associated with androgen insensitivity? |
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Definition
| A mutation of the androgen receptor gene located on the long arm of the X chromosome (Xq21.3) that results in no androgen receptor protein being produced. |
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