Chromosome Abnormalities

Question 1

What aspects of chromosomes are conserved between organisms and what aspects are not conserved?

Answer 1

Chromosome structure, and chromatin composition and architecture may be conserved between species. Number and size of chromosomes and gene density may not be conserved between species.

Question 2

What are the functions of chromosomes/chromatin?

Answer 2

Chromosomes are structural units of DNA, responsible for protecting DNA from damage and regulating gene transcription. They also serve as the units of replication during mitosis and meiosis. Chromatin describes the lower order chromosome structure, and includes DNA and associated proteins.

Question 3

Does size or number of chromosomes matter?

Answer 3

Chromosome number varies between species but is not well correlated with total amount of DNA. Chromosome size may not represent the number of genes encoded in the genome, as smaller chromosomes may be relatively gene dense (e.g. chromosome 19).

Question 4

What kinds of chromosome abnormalities arise in humans and how common are they? What is the impact on development?

Answer 4

Aneuploidy, inversions, translocations, copy number variants (deletions, insertions, duplications), small insertions and deletions (indels) and single nucleotide variants, which may or may not impact development.

Question 5

Which can survive to term? Which are lethal and result in miscarriage?

Answer 5

Although most autosomal trisomies result in spontaneous abortion, trisomies of chromosome 13, 18 and 21, and rare cases of triploidy, can survive to term. Most sex chromosome aneuploidies, including XXX, XXY, XYY and X, can also survive to term. All autosomal monosomies and trisomies of chromosomes 1, 11 and 19 are rare in clinical pregnancies and may be lethal prior to implantation.

Question 6

What types of chromosome abnormalities might occur in a) a healthy adult, b) a child with developmental delay, c) a newborn with major congenital malformations, and d) a first trimester miscarriage?

Answer 6

a) structural variants (e.g. balanced translocation), b) copy number variation, c) trisomy of chromosomes 13, 18 or 21, sex chromosome aneuploidy or triploidy, and d) most autosomal trisomies.

Question 7

How common are chromosome abnormalities in humans?

Answer 7

In humans, aneuploidy occurs in around 20% of oocytes, 2-5% of spermatocytes and more than 20% of all conceptions.

Question 8

What are the possible outcomes of a 45,X/46,XY embryo?

Answer 8

45,X/46,XY mosaicism, also known as mixed gonadal mosaic, results from Y-chromosome mosaicism and leads to abnormal gonadal development. Although it may result in ambiguous genitalia at birth, most affected individuals have normal male genitalia.

Question 9

What are the possible outcomes of a A trisomy 18 embryo?

Answer 9

Trisomy 18, or Edwards syndrome, occurs in around 1 in 6,000 live births. Edwards syndrome is associated with many physical abnormalities and is often fatal, with most individuals failing to survive longer than six months.

Question 10

Why do you think trisomy is more common than monosomy in clinical pregnancies?

Answer 10

In monosomic conceptions, haploinsufficiency, imprinting, and somatic loss of single gene copy may lead to embryonic lethality.

Question 11

22q11.2 deletions can have very variable phenotype in different individuals. What factors might cause phenotypic variability amongst carriers?

Answer 11

The cause of phenotypic variability associated with 22q11 deletion syndrome is not well understood. Variability does not appear to be associated with deletion size, although the specific genes that are lost, particularly in the critical region, may determine in part the penetrance of certain clinical manifestations. Other possible sources of variability may involve other genetic factors, such as modifier genes, or environmental factors.

Question 12

What is a Robertsonian translocation?

Answer 12

A Robertsonian translocation occurs between two acrocentric chromosomes, including chromosomes 13, 14, 15, 21 and 22, resulting in loss of the p arms. The most common form, occurring in around 75% of cases, involves chromosomes 13 and 14.

Question 13

What is a copy number variant (CNV)? How common are CNVs, and, if detected during prenatal diagnosis, how can we predict the effect on fetal development?

Answer 13

CNVs are structural variants that involve the gain or loss of genetic material. These may be microscopic, around 3 Mb of greater, or submicroscopic, 50 bp to 3 Mb. CNVs are relatively common, with an average of around 54 CNVs per individual covering 4.8-9.5% of the human genome.

Question 14

Why does trisomy for sex chromosomes survive better than for other chromosomes?

Answer 14

Despite the number of X chromosomes, dosage compensation through gene inactivation on all but one homolog results in mostly viable embryos.

Question 15

What is X-chromosome inactivation?

Answer 15

XCI is the process through which gene expression is regulated in female cells to achieve dosage compensation. While choice of the inactivated chromosome is random, around 10% of genes on the inactivated chromosome remain active.

Question 16

Why can a triploid survive, though rarely, while individual trisomies (e.g. trisomy 19, trisomy 11) do not survive to implantation?

Answer 16

This may be due to an overall balance of gene expression compared to relative increases in gene dosage with individual trisomies.
the body can better tolerate a balanced increased of gene expressed over an unbalanced increase

Question 17

Some deletions/duplications are recurrent, meaning they occur more often than chance and often enough to be recognized as a syndrome. Why might that be?

Answer 17

Breakpoint regions may contain low-copy repeats or other repetitive elements that are more susceptible to messy DNA repair, such as through non-allelic homologous recombination.

Question 18

How does trisomy arise? How do structural rearrangements arise?

Answer 18

Trisomy may arise by nondisjunction, or the failure of chromosomes to segregate normally during cell division. Structural rearrangements may in general result from improper DNA repair.

Question 19

Why is aneuploidy so common in humans?

Answer 19

Meiosis, in females in particular, is error-prone. In addition, oocytes may remain arrest for decades in humans before completing meiosis at fertilization, allowing for more opportunity for genetic mutation or protein degradation over time.

Question 20

Increased maternal age is the strongest risk factors for miscarriage. Give two independent potential factors that could help explain this and explain how.

Answer 20

Errors in recombination and segregation are associated with maternal age. Aberrations in spindle formation and chromosome alignment are observed in older oocytes that may result from degradation of key proteins involved in recombination, synaptonemal complex formation or other supportive processes.

Question 21

At what point in development does recombination take place during oogenesis? Keeping this in mind, how might altered recombination relate to age-related aneuploidy?

Answer 21

Recombination occurs during meiosis metaphase I, between the pachytene and diplotene phases. Over time, loss of cohesion may be lost and chromosome missegregation may occur as a result. Specifically, cohesion between homologous chromosomes is lost besides at sites of recombination, suggesting that reduced recombination is associated with most trisomies. Failure of recombination, cohesion or spindle complex formation may all lead to meiotic errors.

Question 22

List four differences between oogenesis and spermatogenesis. How might these differences help explain the higher incidence of aneuploidy in oocytes vs. spermatocytes?

Answer 22

A number of differences exist between oogenesis and spermatogenesis: each primary spermatocyte produces four sperm, while each primary oocyte produces one egg; meiosis begins at puberty in males and continues throughout life, while oogenesis begins before birth and arrests until puberty where meiosis is completed at fertilization; the number of sperm reduces slightly over the lifetime, while the number of oocytes is continually depleted until menopause is reached; oogenesis is associated with higher rates of recombination and is more error-prone than spermatogenesis.

Question 23

If we see gain or loss of a sister chromatid in the first polar body (i.e. there was precocious sister chromatid separation), what points of cohesion must have failed for that to occur?

Answer 23

Cohesion between sister chromatids at the centromere must have failed in this case.

Question 24

What are some examples of abnormalities that may be associated with reduced fertility in carriers?

Answer 24

Several chromosome abnormalities may be associated with reduced fertility in carriers, including Robertsonian translocations, balanced translocations, XXY males and X females.

Question 25

Why do males experience more infertility and females more pregnancy loss?

Answer 25

Healthy males have a 1-2% rate of aneuploidy and 6-7% rate of structural abnormality, consistent with most chromosomal abnormalities occurring post-meiotically. Structural variants may be repaired after fertilization, or if not, may result in spontaneous abortion. Constitutional structural abnormalities are common in infertile men, occurring in 2-14%, and increase the frequency of chromosomally abnormal sperm. Note: Over 10% of all human oocytes contain at least one crossover-less bivalent, and half of all such bivalents are expected to result in aneuploidy. Compared to oocytes, synapsis may have an additional level of control in spermatocytes, where errors result in meiotic arrest and sterility. Meiotic sex chromosome inactivation (a general and male version of XCI) is essential for male fertility and may explain additional sensitivity to unsynapsed chromosomes in spermatocytes, whereas synaptic defects result in elimination of some, but not all, oocytes. In many situations, female fertility is maintained, whereas the male is sterile. This suggests that pachytene checkpoint mechanisms are less stringent in the female and that differences in sex chromosome activity during meiosis are likely to underlie the differences between the sexes, although more studies are needed.

Question 26

Why is conventional G-banding karyotyping developed in the 1970’s still the main diagnostic tool for chromosome abnormalities? What other methods can be used to diagnose chromosome abnormalities?

Answer 26

Compared to molecular techniques, G-banding is better at detecting balanced chromosome rearrangements and may avoid the technical challenges or artifacts inherent to current technologies. Fluorescent in situ hybridization (FISH), array comparative genome hybridization (aCGH), SNP array and sequencing can also be used to diagnose chromosome abnormalities.

Question 27

Chromosomal microarray and chromosome karyotyping are two approaches to diagnosing chromosome abnormalities. What are the advantages/disadvantages of each?

Answer 27

Some advantages of microarrays include not requiring cells, usable on frozen or paraffin- embedded specimens, avoiding problems of culture failure or maternal contamination in miscarriage samples and the potential to detect smaller changes. Some disadvantages include difficulty in detecting balanced changes, triploidy/tetraploidy or structure of abnormal chromosomes, can have technological challenges and may be more expensive.

Question 28

How might using microarray for prenatal diagnosis be more controversial than using this approach when applied to diagnose developmental delay in children.

Answer 28

Phenotypic consequences, or the clinical significance, of genetic variation may not be known. Prenatal testing is not guided by phenotype, resulting in potential uncertainty of the clinical significance of any genetic findings.