Clinical Genetics Flashcards
How are genetic disorders classified?
- Mendelian disorders - conditions caused by a single mutation; can be autosomal recessive, autosomal dominant or X-linked. Rare with a high recurrence rate.
- Chromosomal abnormalities - the inheritance pattern is not like Mendelian conditions - often empirical; in translations these abnormalities can be inherited. Usually de novo. Affects the overall gene balance. Account for the majority of spontaneous abortions. Multiple organ systems are affected.
- Multifactorial - caused by a combination of genes and environment. More common with a low recurrence rate.
- Mitochondrial disorders - Due to mutations in mitochondrial DNA which is past down from the mother. The mitochondrial genes mostly code for proteins involved in oxidative phosphorylation - and so cause issues in tissues with a high energy demand.
- Somatic mutations - mutations in somatic cells. usually de novo - can lead to mosaicism. Not passed down onto children.
What is the difference between penetrance and expressivity?
Penetrance: The proportion of individuals with a genetic variant that also display phenotypic characteristics. A high penetrance is where everyone with the condition will have the symptoms. The condition is not effected by other genes or the environment.
Expressivity: variation in phenotypic expression when an allele is penetrant.
What is the difference between autosomal dominant, autosomal recessive and X-linked patterns? What is the percentage of a child of a parent with each of these conditions having an affected child if with a normal parent?
Autosomal recessive: The individual must be homozygous for an allele in order to inherit the condition.
The chance is 25% with a 50% of being a carrier.
Autosomal dominant: The individual needs only to have one variant to have the disorder.
The chance is 50%.
X-Linked Patterns: The variant is found on the tail of the X-chromosome missing in the Y chromosome. As a result, it is expresses mainly in males.
The chance is 25% of having an an affected male if the mother is a carrier and the father is normal.
Give an example of a multifactorial inheritance.
Multiple Sclerosis
What is the genetic basis of dominantly inherited familial cancer syndromes?
A hereditary cancer syndrome is present when a person, because of an inherited mutation, has an increased risk of developing certain tumours. In most known hereditary malignant syndromes the elevated cancer risk is due to a mutation of a single gene. The affected genes concerned usually have a controlling function on the cell cycle or the repair of DNA damage. Sporadically occurring are also caused by an increased incidence of mutations in these genes.
What are mitochondrial disorders? Give an example.
The mutation resides on the mitochondrial DNA – contains only 30-34 genes. These genes are usually related to oxidative phosphorylation. They are maternally inherited. Mitochondrial inheritance disorders usually are expresses in cells with a high energy demand.
Example: Leber hereditary optic neuropathy. degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males.
What is the difference between mitosis and meiosis?
Meiosis is used only for the production of gametes. It is reduction division - it reduces the chromosome number to 23. It ensures every gamete is genetically unique through cross-over and independent assortment. Each homologue replicates to give two sister chromatids.
Mitosis: Normal cell division, produces daughter cells that are genetically identical to the parent cell.
What is cross over?
In Prophase I, the homologous chromosomes pair together. They cross over enabling genes to shuffle between the chromosomes, thereby producing genetically unique chromosomes. This forms a chiasma.
What is the structure of chromosomes?
Centromere - is the specialised DNA sequence of a chromosome that links a pair of sister chromatids
Telomere - is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighbouring chromosomes.
‘p’ arm - short arm
‘q’ arm - long arm
The chromosome is DNA wrapped tightly around histone proteins, RNA and non-histone proteins.
Light band - replicate early in S phase; less condensed chromatin; transcriptionally active gene and GC-rich
Dark band - replicate late; contain condensed and chromatin AT-rich
Give examples of Mendelian inheritance.
Autosomal dominant: Huntington’s disease
Autosomal recessive: Familial Hypercholesterolemia (common - major risk for CVD), Cystic Fibrosis (Quite common - recurrent infection and pulmonary disease), Centennial deafness
X-Linked Disorder: Haemophilia
Duchenne Muscular Dystrophy (Weak muscles, causing the individual to stand using Gower’s manoeuvre)
Fragile X Syndrome
How do you draw a family Pedigree?
- Each generation is labelled by a roman numeral
- The children are order by number from left to right
- Write their date of birth also underneath
- Start from bottom and build up starting with the index child (proband) and their siblings
- Ask about miscarriages, still births or death in each partnership - important to see if there is the possibility of chromosomal abnormalities - often incompatible with life
Ask awkward questions: Ask if there are other children with other partners. Ask about consanguinity - a feature of autosomal inheritance.
What is Mendel’s I Law?
The Law of Segregation ‘The allele of a given locus segregate into separate gametes’
What is Mendel’s II Law?
The Law of independent assortment ‘The alleles of a given locus segregate into separate gametes’
This is how we increase genetic diversity.
What is Mendel’s III Law?
The Law of Dominance ‘One of the factors for a pair of inherited traits will be dominant, and the other recessive, or both recessive’
What issue can occur with the pairing of homologous chromosomes?
There are regions on chromosomes that look very similar and so chromosomes that are not homologous can pair up causing translocation.
What are Acrocentric chromosomes?
Chromosomes 13,14,15,21 and 22.
These chromosomes do not have a ‘p’ arm but instead have a short repetitive sequence - usually encoding rRNA and tRNA. Acrocentric chromosomes, can line up incorrectly such as 13 and 21 which is common translocation event.
What is heterochromatin?
Tightly packed form of DNA that is genetically inactive. Chromosome 1,9 and 16 have heterochromatin at the top of their chromosome.
What is the smallest chromosome?
21
Explain common chromosomal abnormalities relating to number.
Aneuploidy: Aneuploidy is the presence of an abnormal number of chromosomes in a cell. e.g. Trisomy 21 is three copies of chromosome 21. Monosomy is a deletion of a chromosome and so there is only one copy of the chromosome e..g Turner’s Syndrome.
Polyploidy: When there is more than two copies of whole sets of chromosomes e.g. triploidy is 69 chromosomes. This is incompatible with life.
Mosaicism:
When there are cells in the body with different chromosome numbers. This is due to a disruption of meiosis I, meiosis II or mitosis. This is due to errors in the formation of the metaphase plate and so produces different populations of somatic cells e.g. Can produce a milder form of Down’s syndrome.
What are the two types of chromosome translation?
Robertsoniain translation:
When the ‘q’ arm of a chromosome fuses with another chromosome, losing a ‘p’ arm. Since there is so much repetition of the RNA genes, there isn’t an overall change in gene dosage and so will not have an effect on the child. This is the most common form of chromosomal translocation - it does not usually cause health difficulties but can lead to an inherited form of Down’s syndrome and Patau’s Syndrome.
Reciprocal translocation:
Exchange fragments between non-homologous chromosomes.
How are gametogenesis and non-disjunction linked?
Mitosis I of spermatogonia produces spermatocytes. Meiosis II produces spermatids which mature into spermatozoa. The incidence rate of de novo mutations increase with paternal age as higher mutation rates in males are related to the greater number of germ cell divisions.
There may be a lengthy interval between Meiosis I and Meiosis II as Meiosis II occurs when the oocyte is fertilised (this can be up to 50 years). This time means that there is a lot of opportunity for environmental factors to take effect. Damage to repair mechanisms of the primary oocyte increases the chance of non-disjunction.
What is the Karyotype for:
a) Down’s syndrome
b) Turner’s Syndrome
c) Klinefelter’s Syndrome
d) Edward’s Syndrome
e) Patau’s Syndrome
a) 47, XX + 21
b) 46, X
c) 47, XXY
d) 47, XX, + 18
e) 47, XX, + 13
Give examples of chromosomal structural abnormalities.
Translocations
Deletions
Give examples of chromosomal structural abnormalities.
Most are de novo events occurring in meiosis - very low recurrence risk in future pregnancies.
Translocations
Deletions
Duplications
Inversions
