Lecture 3 - Numerical and structural abnormalities

Question 1

What is exact multiples of the haploid set of chromosomes known as?

Answer 1

Euploidy.

Question 2

Are triploidy and tetraploidy compatible with human life? Are they ever?

Answer 2

No, they result in spontaneous abortion. Other organisms like wheat or dandelions can survive and in fact improve crop harvests and outputs.

Question 3

How are chromosomal mutations denoted?

Answer 3

total number of chromosomes, sex chromosome composition, and then deletion or addition. E.g. 47, XX, +13 (trisomy 13) or 45, XY, -8 (monosomy 8).

Question 4

What is mosaicism?

Answer 4

The result of a mutation that leads to a unique cell line from multiplication of the mutated cell.

Question 5

What are three examples of viable trisomies? What chromosome is affected in each?

Answer 5

Down syndrome - 21
Patau syndrome - 13
Edwards syndrome - 18

Question 6

What are the clinical features of Down syndrome?

Answer 6

Short height, low set ears, up slanting eyes, protruding tounge/microcephaly, flat facies, mental retardation, infertility (usually). More prone to system defects incluing leukemia and Alzheimer’s disease.

Question 7

What are the clinical features of Patau syndrome?

Answer 7

Cleft lip, rocker bottom feet, polydactyly, missing hair from top of scalp, heart defects, overall failure to thrive (most die within a year of life).

Question 8

What are the clinical features of Edwards syndrome?

Answer 8

Diminished chin, IV septal defect, muscle hypoplasia, “hand sign,” and failure to meet normal developmental milestones. Most perish in early 20s.

Question 9

What are some variations in sex chromosome combinations that are compatible with life?

Answer 9

Klinefelter - XXY
XYY male
XXX female
Turner - X

Question 10

How do triple X femailes present clinically? How does it usually occur?

Answer 10

They present as average to tall women, potential learning deficits, and/or fertility problems. Most go undiagnosed, and are usually detected in fertility clinics. This geneotype usually happens from meiosis I error.

Question 11

How do XYY males present clinically? How does it usually occur?

Answer 11

They present as tall stature males, with normal intelligence and fertility, and usually go undiagnosed. It usually results as a failure of paternal meiosis.

Question 12

How does Klinefelter syndrome clinically present? How does it usually occur?

Answer 12

Males have tall stature, infertility due to hyalinized testicular tubules, azoospermia, small testicles, female characteristics (breasts and fatty hips), and learning deficits. It usually occurs as a result of paternal meiosis I error.

Question 13

How does Turner syndrome present clinically?

Answer 13

Females have very short stature, webbed neck due to swelling in utero, low posterior hairline, primary amenorrhea, infertility, sometimes learning deficits.

Question 14

How does 45,X/46,XY mosaicism work? Are the offspring male or female?

Answer 14

Males typically appear normal and develop normally while females have more Turner like features including non-functional gonads and ambiguous genetalia. Females are more likely to develop gonadoblastoma. The male or female phenotype is determined based on which cells are more prevalent/active during development.

Question 15

How can Turner syndrome patients height concerns be addressed? infertility?

Answer 15

They can start growth hormone therapy at a very early diagnosis. Infertility can be addressed with egg implantation because the uterus functions normally, it is just follicle development that is abnormal.

Question 16

Describe an XY female (androgen insensitivity).

Answer 16

The Y chromosomes are normal, but the androgen receptor gene on the X chromosome is mutated. TDF on the Y will start male development, but will not be complete due to the inability of testosterone and dihydrotestosterone to bind. The default female pathway is reverted. These patients typically have blind vagina and some male internal genetalia.

Question 17

Describe an XX male (21a-hydroxylase deficiency).

Answer 17

It is also known as congenital adrenal hyperplasia. Due to the defective 21a-hydroxylase, androgens buildup and levels can cause male appearing infant, despite the XX chromosomes. Mothers with CAH can have problems with their female fetus due to high circulating levels of androgens.

Question 18

How can a XX geneotype give a male phenotype? What region is incorrectly crossed over?

Answer 18

XX genotype can result in male phenotype when the SRY gene is incorrectly recombined, being so close to the pseudoautosomal region. The opposite can happen with the Y (free of SRY/TDF) being transmitted, resulting in a Turner phenotype.

Question 19

What are the two types of structural chromosomal abnormalities?

Answer 19

Balanced and unbalanced.

Question 20

What is it called when part of a chromosome is missing? What are the two types?

Answer 20

Deletion - resulting in partial monosomy. It can be terminal or interstitial (at the end or within).

Question 21

What is a deletion syndrome that results from deletion of the 4p- (short arm) of chromosome 4 resulting in microcephaly, micrognathia, startled expression, and developmental delay?

Answer 21

Wolf-Hirschhorn Syndrome, aka the Greek warrior helmet disease.

Question 22

What is it called where there is the presence of an additional copy of a chromosome? What are the two types?

Answer 22

Duplication - resulting in partial trisomy. It can be terminal or interstitial (at the end or within).

Question 23

What is reciprocal translocation? Does this usually result in a clinical phenotype?

Answer 23

Reciprocal translocation is when non-homologous chromosomes break and exchange pieces of DNA, This is usually benign unless the break happens within a regulatory gene. These carriers are also at higher risk of transmitting chromosomal abnormalities to their children.

Question 24

What are the three types of unbalanced translocation? How do they differ?

Answer 24

1. Adjacent 1 segregation - results in 2 unbalanced with both deletion and replication of some material.
2. Adjacent 2 segregation - homologous centromeres move to the same pole resulting in one with deletions and one with duplications
3. 3:1 segregation - 3 chromosomes end up in one cell (very unnatural and not viable)

Question 25

What is Robertsonian translocation? What type of chromosomes doe it happen between?

Answer 25

It occurs between 2 acrocentric chromosomes and appears as a fusion of the long arms of the chromosomes. It results in the loss of both short arms, but these genes are preserved on the other set of non-recombinant chromosomes.

Question 26

What is the clinical significance of Robertsonian translocation?

Answer 26

Those affected do not show clinical manifestations, but become more likely that they pass non-disjunction errors to their offspring. e.g. trisomy 13 (non-homologous Robertsonian translocation). Those individuals with homologous Robertsonian translocation usually are infertile, due to the passing of either 2 copies or 1 copy of a chromosome which is incompatible with life.

Question 27

What is it called when there is a reversal of a chromosomal segment in comparison to the normal gene arrangement? What are the two types?

Answer 27

Inversion - requires a minimum of two breaks in the genetic material. It can be pericentric (opposite sides of the centromere) or paracentric (same side of the centromere).

Question 28

What is the mechanism for inversion? What are two clinically manifesting outcomes?

Answer 28

The chromosomes create an inversion loop. The two outcomes can either be dicentric (resulting in cell death) or acentric (contains no chromosomes).