Numerical and Structural Abnormalities

Question 1

Euploidly

Answer 1

-exact multiples of a haploid set

Question 2

Triploidly

Answer 2

• triploidy and tetraploidy are not compatible with life and are detected primarily in spontaneous abortus tissue
• may be due to the failure in gametogenesis of one of the meiotic divisions giving rise to a 2N gamete and is then fertilized by a haploid gamete
• or dispermy- the fertilization of a haploid egg by two sperm and this generally results in a partial hydatidiform mole

Question 3

Tetraploidy

Answer 3

• 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
• hexaploidy goes work in wheat

Question 4

Aneuploidy

Answer 4

• gain or loss of chromosomes equaling less than one complement
• most aneuploidies are incompatible with life and will terminate spontaneously. The only viable monosomy is of the X chromosme (45, X
• usually not inherited but are due to meiotic or mitotic nondisjunction errors

Question 5

Nomenclature

Answer 5

• to describe a chromosome complement
• the total number of chromosomes
• the sex chromosome complement
• any chromosome abnormalities
• they are listed in order
• 46, XX normal female
• 46, XY normal male
• Trisomy 13: 46, XX, +13
• Monosomy 8: 45, XY, -8
• Sex chromosome 45,X and 47, XXY
• if gain or loss of a sex chromosome change is seen in cancer cells, a + or - would be used to indicate the acquired change

Question 6

Meiotic Nondisjunction

Answer 6

• 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 chromosme (A1 and A2), fertilization with a normal gamete (A5) will result in trisomy for the A chromosome

Question 7

Mosaicism

Answer 7

• presence of at least 2 different cell lines with at least one clear variation between them
• numerical change 45,X and 46, XX
• structural change: one cell line with a translocation that doesn’t occur in the other
• is acquired cant be inherited
• usually the two cell lines differ by this single change
• a chimera also has two different cell lines but usually the two have many differences which can be traced back to the original two cells

Question 8

-Visable Autosomal Trisomies

Answer 8

• Down syndrome: trisomy 21
• Patau syndrome: trisomy 13
• Edwards syndrome: trisomy 18

Question 9

Trisomy 21

Answer 9

• Down syndrome
• Incidence 1/700
• short stature
• low set ears
• microcephaly
• mental retardation
• up slanting eyes
• short hands
• eye folds
• protruding tongue
• usualy infertile

Question 10

Multiple System Defects in Down Syndrome

Answer 10

heart

• lung
• brain
• endocrine system (infertile)
• susceptibility to infectious disease (15X)
• increased risk of leukemia (10X)
• high frequency of Alzheimers disease
• more problems may arise as individual ages

Question 11

Trisomy 13

Answer 11

• Patau syndrome
• failure to thrive
• cleft lip and palate
• rocker bottom feet
• polydactylyl
• punched out scalp
• small head
• heart defect
• 1/4000 to 1/10,000

Question 12

Trisomy 18

Answer 12

• Edwards syndrome
• 1/8000 live births
• low birth weight
• small mouth/jaw
• ventricular septal defect
• hypoplasia of muscles
• prominent occiput
• low set malformed ears
• rocker bottom feet
• crossed fingers
• usually die within the first month of life

Question 13

Sex Chromosome Aneuploidies

Answer 13

• Klinefelter syndrome: 47, XXY
• XYY male
• XXX female
• Turner syndrome: 45,X
• phenotypically milder than autosomal aneuploidies due to the effect of X inactivation and the limited number of genes present on the Y chromosome
• all are a result of a nondisjunction errors in meiosis and except for XYY which is exclusively paternal, the other disorders may result from either materal or paternal error

Question 14

XXX Female

Answer 14

• 1/1000 female live births
• usually due to maternal meiosos I error
• average to tall stature
• learning deficit possible
• some fertility problems possible

Question 15

XXY male

Answer 15

• 1/1000 male live births
• failure of paternal meiosis
• tall stature
• normal intelligence
• normal fertility
• clinical indistinguishable from 46, XY
• criminal tendencies??

Question 16

Klinefelter syndrome

Answer 16

• 1/1000 male live births
• 50% due to meiosis I error in father
• tall stature
• infertility
• some female characteristics may develop
• learning deficit possible
• hyalinized testicular tubules

Question 17

Turner Syndrome

Answer 17

• incidence 1/5000 live female births
• short stature
• webbed neck ( in utero- cystic hygroma)
• at birth, edema of 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
• about half the patients have 45, X karyotype
• 15% have deletions or rearrangements of the X
• 10% are mosaics

Question 18

45,X/46,XY mosaicism

Answer 18

• may have a male or female phenotype
• male phenotype usualy okay
• female (Turner) phenotype- high probability of a problem- increased risk of gonadoblastoma (a lethal gonadal tumor)- remove it

Question 19

Turner syndrome issues

Answer 19

• growth hormones
• monitor for heart malfunctions
• karyotype to be sure no Y chromosome is present
• counseling for probable infertility: possibility of pregnancy with donor egg

Question 20

XY Female

Answer 20

• 1/20,000 live births
• androgen insensitivity
• phenotypically normal female with testes
• infertility
• the Y chromosome is intact and the TDF is present and function, the problem is a mutation of the androgen recepto gene located on the long arm of the X chromosome so that no androgen receptor protein is 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

Question 21

XX “Male”

Answer 21

• congenital adrenal hyperplasia
• autosomal recessive condition
• mutation results in overproduction of androgens in female fetus
• in utero exposure causes virulization of fetus : normal ovaries and internal genitalia, ambiguous external genitalia
• can be due to CAH in mother or fetus (lack enzyme 21-hydroxylase)

Question 22

XX Male

Answer 22

• 1/20,000 live births
• XY recombination near pseudoautosomal region
• usually normal, possible Klinefelter phenotype
• the reciprocal translocation (TDF/SRY is replaced by Xp material which is transmitted to a child) results in a Turner female phenotype with an apparent 46, XY karyotype

Question 23

XY Gonadal Dysgenesis

Answer 23

• 46,XY Disorder of Sex Development (male or female)
• ambiguous genitalial with mild to severe penoscrotal hypospadias with or without chordee
• dysgenetic testes
• reduced to no sperm production
• Mullerian structures that range from absent to presnce of a fully developed uterus and fallopian tubes
• 46, XY Complete Gonadal Dysgenesis (female Turner features)
• a 46, XY Karyotype
• normal female external genitalia
• completely undeveloped (“streak”) gonads
• no sperm or egg production
• presence of normal Mullerian structures

Question 24

Structual chromosome rearrangments

Answer 24

• deletion
• duplication
• translocation
• inversion

Question 25

Balanced/ Unbalanced

Answer 25

- balanced- all the material is present but reannged - unbalacned- some of the material is missing or duplicated - balanced usually fine but may increase the risk of errors in meiosis resulting in chromosomal imbalances in fetuses or live born children. It is possible for a balanced translocation to result in clinical abnormalities IF one of the breaks occurs within a gene resulting in its loss of function - unbalanced chromosome complements are generally associated with an abnormal clinical phenotype that often included developmental delay and mental retardation

Question 26

Deletion

Answer 26

- loss of a part of a chromosme - leads to partial monosomy - the severity of consequences depends on the size of the deletion and exactly what genes/alleles are lost - some deletions have been shown to occur repeatedly resulting in a consistent phenotype- particular syndrome

Question 27

Terminal deletion

Answer 27

- the distal end of one arm of a chromosome is lost - requires only 1 break - loss of end of short arm of chromosome 4 Wolf-Hirschhorn syndrome

Question 28

Interstitial deletion

Answer 28

- an internal region of the chromosome is lost | - requires two breaks

Question 29

Wolf- Hirschhorn syndrome

Answer 29

- microcephaly - micognathia - hypotonia - epicantal folds - startled expression - arched brows - long nose with squared off end - short stature - developmental delay - deletion terminal of the short arm of chromosome 4

Question 30

Deletions

Answer 30

- loss of one or more genes usually leads to clinical abnormalities - small deletions may be tolerated with minimal clinical abnormalities - large deletions typically associated with development delay, mental retardation, abnormal features - size is not as important as which genes and how many are missing

Question 31

Duplication

Answer 31

- an additional copy of a chromosome segment that leads to partial trisomy for that chromosome - similar to deletions, duplications can be either terminal or interstitial - terminal duplications have extra material at one end of the chromosme- usually a copy of adjacent regions - this type of abnormality is usually sporatic though it could be inherited from a parent with a benign chromosome rearrangement

Question 32

Cornelia de Lange syndrome

Answer 32

- often due to long arm of one chromosome 3 - short - developmentally delayed - excess hair hirsute - missing distal arms or legs - characteristic facial feature that make these patients more similar to each other than their family - synophrys- fusion of eyebrows

Question 33

Translocation

Answer 33

- rearrangements involving two or more nonhomologous chromosomes - each chromosome breaks once and the pieces exchange places, producing two or more derivative chromosomes - in a balanced translocation all of the DNA is retained just moved - as long as the breaks do not occur within an important coding gene, the rearrangment should be clinically benign - can figure it out by looking at banding

Question 34

Balanced translocation

Answer 34

- increased risk that another pregnancy will have an unbalanced chromosome complement - increased risk of infertility or spontaneous fetal loss - increased risk of an abnormal live born (10% ) - 1/5000 - carriers usually phenotypically normal - may be inherited or de novo

Question 35

Robertsonian Translocation

Answer 35

- centromere to centromere translocation involving acrocentric chromosomes - may between nonhomologus or homologous - loss of both short arms (repeat copies of the rRNA genes) but because this material is present on the remaining 8 acrocentric chromosomes, the loss as a result of the translocation is not deleterious - can be problems with meiosis resulting nondisjunction errors

Question 36

Inversion

Answer 36

- reversal of a chromosomal segment with respect to the normal gene arrangment - two breaks at least - most are balanced - peither pericentric or paracentric

Question 37

-Pericentric

Answer 37

- breaks occur on opposite sides of the centromere and the segment reverses order generating a new chromosome with the same genes in a different order - due to presence of the centromere within the inverted segment, the chromosome morphology may change

Question 38

Paracentric

Answer 38

- the two breaks occur on the same size of the centromere such that the centromere is not involved in the rearrangement - unless the break occurs within important structural genes, an inversion will most likely be clincally benign - sometimes twist with inversion loop

Question 39

Inversion loop

Answer 39

- for a paracentric inversion in order for the chromosome to pair properly, one of the chromosomes must twist resulting in an inversion loop - in the absence of recombination, the meiotic divisions will occur normally and gametes either with or without inverted chromosome will be produced - if recombination occurs within inversion loop- abnormal chromosomes are formed - dicentric- two centromeres, unstable and with break generating deletion - acentric- no centromeres and can't participate in cell division, it eventually will be lost - Not suppressing recombination but it is occuring but cannot be detected because the recombinant products have been lost

Question 40

Large/small inversion

Answer 40

- larger inversion more viable gametes | - smaller inversion greater risk of unbalanced gametes

Question 41

Multiple chromosomal abnormalities

Answer 41

- either numerical or structural, that result in an unbalnced chromosome complement are usually associated with some type of abnormal clinical finding, and the size of the imbalance tends to be proportional to the severity of the problem - very rarely patients will be found with 2 chromosome abnormalities - the first is consistent with Turner syndrome and the second with Prader-Willi/Angelman syndromes

Question 42

Paternity

Answer 42

- critical to know who the biological father is - interpretation of data may reveal that the husband is not the father of the child - if the data input is false, interpretation of the data may be compromised

Question 43

Importance of Karyotype Analysis

Answer 43

-identify chromosomal anomalies that may be associated with disease and be able to distinguish normal variation from true abnormality