MCG - Genetic Basis of Disease Flashcards
What are the different types of human genetic variations?
- SNV, Single Nucleotide Variant:
a difference in a single nucleotide. - (STR, Short Tandem Repeats:
recurring elements of DNA made up of 2-6 bases.) - (Small Indels:
insertion and deletions involving between 1 and 999 nucleotides.) - CNV, Copy Number Variant:
insertion, deletions, inversion and duplications of greater than 1,000 nucleotides. - Chromosomal Variation:
variation in chromosome number, multiple sets of chromosome.
What is considered a rare variant?
A variant is considered rare when the minor allele frequency (MAF) is less than 1% in the population.
When pathogenic, they are also named mutations.
What are the different types of genetic diseases?
Single Gene disease- Mendelian disease:
A disorder caused by abnormality or mutation in the sequence of one gene.
Multifactorial disease-Complex disease:
A disease caused by a combination of SNPs in multiple genes and the influence of the environment.
Chromosomal Disease:
Abnormalities in chromosome structure or extra copies.
Mitochondrial disease:
A disease caused by a mutation in the non chromosomal DNA of the mitochondria.
Give an example for all genetic disease types.
Single Gene disease- Mendelian disease:
- cystic fiborisis
- Huntington’s disease
Multifactorial disease-Complex disease:
- psoriasis
- Chron’s disease
Chromosomal Disease:
- Trisomy 21 aka. Down’s Syndrome
Mitochondrial disease:
- mitochondrial myopathy
Define penetrance.
Penetrance is the proportion of individuals with the mutation who exhibit clinical symptoms among all individuals with such mutation.
For example, if a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not.
Describe the disease cystic fibrosis.
It affects ~11,000 people in the UK.
It is characterized by abnormal levels of thickened mucus gathering in the lungs, digestive system and other organs.
The build-up of mucus in the airways leads to breathing problems, recurrent respiratory infections, and permanent damage.
The affected patients normally get a bowel obstruction in the first few days of life.
Symptoms:
- malnutrition
- daibetes
- osteoporosis
- liver problems,
- reproductive problems
- arthritis
Describe the inheritance of cystic fibrosis.
It is Mendelian, and follows autosomal recessive inheritance.
The affected individuals carry two copies of mutant allele.
Individuals with one copy are healthy carriers.
Offspring have 1 in 4 chance of inheriting the disease from two carrier parents.
What is the most common mutation that causes cystic fibrosis, and how does it do so?
The prevalent mutation in CFTR is ΔF508, a
deletion of 3 nucleotides, resulting in the loss of the amino acid phenylalanine (F) at the 508th position on the protein.
There are 1700 more less common mutations in CFTR
Mutations in CFTR reduce the ion channel’s functioning: the protein is misfolded and trapped in the endoplasmatic reticulum and when it manages to reach the cell membrane it is not active.
This disrupts the transport of water and salts through the cells of the epithelium, and causes the abnormal levels of thick mucus, which end up obstructing the lungs and other organs.
Where are we now with the management/ treatment of cystic fibrosis?
We now have:
- new born screening for the mutation
- carrier testing
- the median survival age is now 47
We also have several drugs targeting the disease:
- Ivacaftor (2012)
- Ivacaftor-lumacaftor (2015)
- Ivacaftor-tezacaftor (2018)
- Ivacaftor-tezacaftor-elexacaftor (2019)
Describe the disease Huntington’s disease.
It is a progressive neurodegenerative disorder. It has a prevalence of 4-5 per 100,000 in European populations.
Symptoms include:
- personality changes
- motor impairment
- chorea (ceaseless rapid complex body movements that look well coordinated and purposeful but are involuntary)
- dystonia (a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures)
- tremor
- cognitive impairment
- depression
- irritability
It normally has a juvenile to adult age of onset (35 and 60 yrs old). It lasts for a duration of 15 - 20 years.
Normally, the HDD (Huntingtin) contains between 6 to 35 copies of the CAG repeats. The increase of CAG repeats directly correlates with the likelihood of disease occurrence, and inversely correlates with the age of onset.
The mutated protein being toxic for the neurons, causing neuron degeneration.
There is no effective disease therapy.
Describe the inheritance of Huntington’s disease.
It follows autosomal dominant inheritance.
Affected individuals carry one copy of the mutant allele.
Offspring have a 50/50 chance of inheriting the disease.
Where are we now with the management/ treatment of Huntington’s?
Genetic testing now allows for pre- symptomatic diagnosis, pre-natal screening and pre-implantation genetic diagnosis.
What is a genome-wide association study (GWAS)?
It is an analysis of the genome-wide set of common variants in cases and controls to evaluate if any variant is statistically associated with the disease.
The association is based on p-values.
The lower the p-value, the stronger the association between a variant and a disease.
What are some limitations of GWAS?
- GWAS can identify SNPs associated with a disease, but they cannot identify which SNP or gene is causal as many SNPs are often co-inherited together.
- It is more correct to refer to an associated locus than to a specific SNP or gene.
- Functional studies aimed at understanding the biological role of the association are needed.
- The associations are often very weak, but while they may not explain much of the risk, they provide insight into genes and pathways that can be important for the disease and can be targeted by drugs.
Describe the disease psoriasis.
It is an immune-mediated, chronic inflammatory skin disease affecting 2-3% of European population.
It is characterized by red, inflamed scaly plaques, due to excessive keratinocyte proliferation, and immune cells activation.
Comorbidities include:
- psoriatic arthritis
- obesity
- cardiovascular disease (CVD)
- inflammatory bowel disease (IBD)
- depression
It is a complex etiopathogenesis resulting from the interaction of genetic susceptibility, environmental triggers and aberrant immune activation.
Therapies span from topical to systemic immunomodulatory drugs, according to the severity of the disease. There is no cure, but the disease is managed.
