Lecture 9 - Chromosomal abnormalities

Question 1

What are the sex chromosome aneuploidies?

Answer 1

Klinefelter syndrome (47, XXY), XYY male, XXX female, Turner syndrome (45, X)

Question 2

Describe XXX females

Answer 2

1/1000 female live births, usually due to maternal meiosis 1 error, average to tall, learning deficit possible, some fertility problems

Question 3

XYY males

Answer 3

1/1000 male live births, failure of paternal meiosis, tall, normal intelligence/fertility, clinically indistinguishable from 46,XY

Question 4

Klinefelter syndrome

Answer 4

47, XXY - 1/1,000 male live births, 50% due to meiosis 1 error in father, tall, infertility, some female characteristics, learning deficit possible

Question 5

Turner syndrome

Answer 5

45,X - 1/5000 live female births, short stature, short hands and fingers, normal intelligence (may have learning difficulties), webbed neck, heart problems, usually infertile - 50% of patients have 45,X, 15% have deletions of X, 10% mosaics

Question 6

Do individuals with 45,X/46,XY mosaicism have male or female phenotype?

Answer 6

It depends! Males are usually okay. Women (Turner) - high probability of problem - gonadoblastoma

Question 7

XY female

Answer 7

1/20,000 live births, androgen insensitivity, phenotypically normal female w/ testes, infertile - mutation of androgen receptor gene on X chromosome

Question 8

XX “male”

Answer 8

congenital adrenal hyperplasia, autosomal recessive, overproduction of androgens in female fetus, ambiguous external genitalia, can be due to CAH in mother

Question 9

XX male

Answer 9

1/20,000 live births, X-Y recombination near pseudoautosomal region, usually normal - if rearranged X chromosome passed to offspring could result in a turner female

Question 10

Possible structural changes to chromosomes

Answer 10

Deletion, Duplication, Translocation, Inversion

Question 11

Balanced vs Unbalanced abnormalities

Answer 11

Balanced - all material present but rearranged (normally clinically benign) … Unbalanced - some of the material missing or duplicated, abnormal phenotype

Question 12

Deletion

Answer 12

loss of a part of a chromosome, leads to partial monosomy - terminal deletion (end lost) vs interstitial (internal region lost). Severity depends not as much on size of deletion but which genes and how many are missing

Question 13

Wolf-Hirschhorn Syndrome

Answer 13

4p- deletion - microcephaly, “greek warrior helmet”, require special education, increased risk for seizures

Question 14

Duplication

Answer 14

additional copy of a chromosome segment, results in partial trisomy - normally pretty rare

Question 15

Translocation

Answer 15

equal exchange involving two or more chromosomes - as long as the breaks don’t occur within an important coding gene, the rearrangement should be benign - can cause shit for offspring though

Question 16

Balanced translocation facts

Answer 16

1/500, usually phenotypically normal, translocations can be inherited, or can be de novo (karyotyping is important!)

Question 17

Significance of a balanced translocation for an individual?

Answer 17

Increased risk another pregnancy could have unbalanced chromosome complement, increased risk of infertility or spontaneous fetal loss, increased risk of abnormal live born

Question 18

Robertsonian translocation

Answer 18

Occur only between two acrocentric chromosomes and appear as a fusion of the long arms at the centromere - may be between nonhomologous chroms (13 and 14) or between homologous chroms (13 and 13) - results in loss of rRNA genes on chroms, but is present elsewhere = not deleterious (45 chromosomes but normal)

Question 19

Risks of robertsonian translocation?

Answer 19

Can negatively impact meiosis resulting in nondisjunction errors (ex. child can inherit trisomy 13 by getting two normal 13s, and a 14 and 13/14)

Question 20

Inversion

Answer 20

reversal of chromosomal segment with respect to the normal gene arrangement - requires minimum of two breaks in one chromosome, often balanced but can be bad if gene interrupted

Question 21

Pericentric vs Paracentric

Answer 21

Pericentric - The breaks occur on opposite sides of the centromere and segment - generates new chromosome with same genes in different order. May change morphology of chromosome (submetacentric to metacentric.

Paracentric - two breaks occur on same side of the centromere

Question 22

Affects of paracentric inversion

Answer 22

Can affect fidelity of meiosis, for chromosomes to pair properly, one of the chromosomes must twist resulting in an inversion loop. Appears if inversion is suppressing recombination

Question 23

Affects of pericentric inversion

Answer 23

Recombination within loop gives rise to recombined gametes with duplication and deletion of gene regions - however, the larger the inversion the more virable

Question 24

Can more than one chromosomal abnormality occur in one person?

Answer 24

YES!

Question 25

What is the importance of karyotype analysis?

Answer 25

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