0226 - Chromosomal Disorders - RM Flashcards
What is a chromosome?
A dense compaction of DNA, localised in the cell nucleus.
How many chromosomes do healthy humans have in each cell?
46 (2n) in diploid (somatic cells), and 23 (n) in haploid (gametes).
What is the prognosis for an embryo with a genetic abnormality?
Errors in the number or structure of chromosomes are generally not compatible with life. Where life remains, major diseases often result.
What is Progeria? How is it caused?
Progeria is a genetic disease that causes premature aging (death around age 13). It is caused by a single base pair mutation in a gene involved in forming cell nuclei.
What is hypertrichosis? How is it caused?
Hypertrichosis (werewolf syndrome) results in uncontrollable hair growth (otherwise healthy individuals). it is caused by a rearrangement of genes in chromosome 8.
What is “Ploidy”?
Ploidy refers to the number of chromosomes in a cell - normal human gametes are haploid (n=23) and somatic cells are diploid (2n=46).
What is Euploidy
It means the affected person has the correct number of chromosomes. Euploidic disorders would thus normally be structural, altering the chromosomes size or information.
What is Aneuploidy
An absence of euploidy. With aneuploidy, the person does not have the correct number of chromosomes. They could have extra chromosomes (trisomy 21) or a missing chromosome (Turner’s Syndrome).
What does it mean if a disease is -somy (e.g. trisomy, monosomy)
It means that the ‘error’ occurs in the duplication or deletion of one chromosome, and the other chromosomes are generally normal (e.g. trisomy 21, monosomy 7).
Why is aneuploidy usually lethal in-utero
In addition to the abnormalities the chromosomal defect may cause, the sheer amount of material required to generate the nucleotides (or left as surplus from the missing material) disrupts equilibrium in the cells to the extent that it is not compatible with life.
When is aneuploidy not lethal in-utero
When one of the smaller chromosomes is duplicated or missing (13, 14, 18, 21, x or y). As these do not require as many nucleotides as a large chromosome, the foetus may survive to birth.
How common is Down Syndrome, and what are five symptoms
1:750 births. It causesCraniofacial defectsCardiac defectsCognitive impairmentReduced HeightReduced life expectancyincreased risk of Alzheimer’s DiseaseLowered Fertility
What is the primary risk factor for Down Syndrome?
Maternal Age, however there is a small correlation with paternal age.
Briefly outline the three types of Down Syndrome
Trisomy 21 - occurs in 90-95% of cases, and results from a duplication of chromosome 21 in either sperm or egg.Mosaic trisomy 21 - occurs in 2-3% of cases, with only some cells containing the trisomy. It is caused by abnormal cell division after fertilisation.Translocation trisomy 21 - occurs in 4-5% of cases, where part of Chromosome 21 transfers to another chromosome (generally 13, 14, 15, or 22). The effected individual may have 46 chromosomes, but the genetic material of 47.
Are chromosomal abnormalities common in human oocytes?
Yes - a study of IVF patients of advanced age found 61.8% of oocytes had an abnormality that could cause aneuploidy in the embryo.
What is trisomy 18
Edwards Syndrome. It occurs in 1:6,000 births, with a very high mortality rate in-utero. It disrupts normal development and causes heart and kidney disorders.
What is trisomy 13
Patau Syndrome. It affects 1:10,000 births, with a very high mortality rate (50% at one month). It often causes fusion of the nose and eye, as well as heart and kidney defects.
What is the primary cause of aneuploidy? What does it result in?
Nondisjunction during meiosis. If it occurs during Meiosis I, all gametes will be affected (2 n+1, 2 n-1). If it occurs in meiosis II, only half the gametes will be affected (2 n, 1 n+1, 1 n-1).
Why is aneuploidy in sex chromosomes tolerated better than in autosomes?
- Females have x-inactivation, so only one X chromosome expresses its genes in a given cell - additional ones are unlikely to compete with each other.2. The Y chromosome is small, if it is duplicated, cell equilibrium is not catastrophically affected.3. Genes on the Y chromosome are not required for survival, so abnormalities are not generally catastrophic.
What are the four sex chromosome disorders? Which are minor and which are major?
XXX and XYY are minor disorders, and do not always present a phenotype. Monosomy X (turner Syndrome) and XXY (Klinefelter Syndrome) are the more major disorders.
What percentage of foetuses with chromosomal abnormalities survive to birth?
5% - almost exclusively with Down Syndrome.
Describe Turner Syndrome
Monosomy X - caused by a missing X chromosome, or rarely, a rearranged second X chromosome. It only effects females, occurring in 1:2,500 births. Carriers can live a comparatively normal life, however it can cause short stature, sexual infantism, an minor or major physical abnormalities.
Describe Klinefelter Syndrome
XXY - an additional X chromosome in males. It occurs in 1:500-1,000 births, and not all carriers develop symptoms. When they occur, symptoms include hypogonadism and increased stature. There is a highly debated link to increased criminality.
What does it mean if a chromosomal rearrangement is ‘balanced’?
It is a homologous recombination (generally caused by chiasma crossover). Balanced rearrangements are omnipresent, and necessary for genetic diversity. They are referred to as balanced because they do not result in a net gain or loss of genetic material, and do not exhibit a phenotype.
What does it mean if a chromosomal rearrangement is ‘unbalanced’?
There is a net gain or loss of genetic material, and a high chance of exhibiting a phenotype. The size of the rearrangement will often determine the consequences.
What are the five basic forms of chromosomal rearrangement?
Deletion DuplicationInversion InsertionTranslocation
Describe ‘deletion’ as a form of chromosomal rearrangement. Give two examples of diseases it can cause
Loss of DNA sequence within a single chromosome - loss of genetic material. Cri du Chat syndrome - deletion of 5p. It causes congenital malformation of the larynx, intellectual disability, delayed development and microcephalyPrader-Willi and Angelman syndromes can be caused by deletion or non-expression of chromosome 15. They cause low muscle tones, short stature, incomplete sexual development, and behavioural problems including excessive eating.
Describe Duplication as a form of chromosomal rearrangement.
Duplicated section within a single chromosome - gain of genetic material.
Why do chromosomal duplications and deletions often occur together?
During meiosis, chiasma crossover often occurs to increase genetic variability. If there is a partial nondisjunction, one chromosome may come away with a duplicate of a particular section, leaving the other chromosome missing it altogether.
Describe inversion as a form of chromosomal rearrangement
Inversion results in the reversal of a section of DNA within a single chromosome. This can occur when genetic material forms an ‘inversion loop,’ so rather than ABCDEF, CDE might form a loop, which when replicated would make it ABEDCF.Inversions are balanced rearrangements, so may not result in a phenotype.
Describe Insertion as a form of chromosomal rearrangements
A sequence of DNA is moved from one chromosome to another, leaving one chromosome shorter, and one longer, but not resulting in a net gain or loss of genetic material.
Briefly describe chromosomal translocation and its two main sub-types.
Translocation occurs when sequences of DNA on two separate chromosomes are swapped with each other. This can cause many diseases, including many cancers. It can also be asymptomatic, resulting only in reduced fertility or zygote abnormalities if gametes are produced with insufficient or excess genetic information.Reciprocal translocations are often asymptomatic and occur when the DNA is swapped, so that the new derivative chromosome carries DNA from both parts.Robertsonian translocations are a distinct form of reciprocal translocation that results in a split at the centromere - the long arms of each chromosome combine, as do the short arms - leaving one very large and one very small chromosome which may be lost.
Describe a Robertsonian translocation
The translocation occurs at the centromere, resulting in one chromosome with two q-arms, and one with two p-arms. It can only occur in the five acrocentric chromosme (13, 14, 15, 21, 22).The short armed derivative chromosome is often lost, leaving the frequently asymptomatic carrier with 45 chromosomes.
