Genetic Disorders Flashcards
What is a Mutation
Permanent change in DNA.
What is affected to cause Inherited Diseases
Mutations that affect germ cells i.e. cells that are transmitted to offspring.
What are Point mutations within coding regions, what are the types, and what are disease examples of this
What it is:
- Single base substituted for a different base.
- Meaning of sequence changed.
Types:
- Missense (altered meaning of sequence).
- Conservative (little change in protein function).
- Non-conservative (different protein function).
- Nonsense (premature STOP).
Examples - Missense:
- Sickle cell disease.
Examples -Nonsense mutation:
- beta0 thalassaemia.
What can mutations within NON-coding sequences cause
- Interference with transcription factor binding –> reduction OR no transcription (e.g. some thalassaemias).
- Defective splicing of intron –> unable to form mature mRNA –> no translation –> no protein.
Deletions and insertions:
- What is the effect of these in coding regions if the number of base pairs is a multiple of three
- What is a clinical example of this
Effect:
- Reading frame remains intact.
- Abnormal protein synthesised.
Example:
Cystic Fibrosis:
- 3 base deletion.
- Result: missing AA 508 - encodes phenylalanine.
Alterations in protein-coding genes other than mutations (Amplifications, deletions or translocations):
-What is the effect of these alterations, and what are some clinical examples
Effect:
- Abberation gain or loss of protein function.
Examples:
- Chronic myeloid leukaemia - t(9;22) Philadelphia chromosome (translocation between BCR and ABL genes on Ch 9 and 22)
- 22q microdeletion syndrome.
- Autism.
- Cancers.
What are Trinculeotide-repeat mutations.
- Amplification of a sequence of three nucleotides.
- Almost always includes G and C nucleotides.
- Dynamic mutation - degree of amplification increases over generations.
Northern Blot
Old technique used to detect select RNA in a sample.
How:
1. RNA extraction.
2. Run on gel (direction of movement is toward positive electrode).
3. Transfer to nylon membrane (RNA negative, membrane positive charge).
4. Fixed to nylon membrane with UV light.
5. Probe hybridisation - probe binds to complimentary RNA.
6. Wash to remove any probes not bound.
7. Radiograph of plot.
Cons of test:
* No amplification of RNA.
Western Blot
Allows detection of specific protein.
How:
1. Extract protein from sample.
2. Add extracted protein to SDS gel with dye - separates protein based on molecular weight (heavier at top, lighter at bottom).
3. . Transfer to PVDF membrane with electrical field.
4. Specific monoclonal antibody added.
5. Colourimetric, chemiluminscence or fluorescence used to detect any protein bound to antibody (antibody tagged depending on method so can be detected).
Use:
* Detect infectious agents e.g. HIV.
* Study cell signalling.
Metabolic conditions:
-Usual inheritance pattern, dose effect, and phenotype correlation
Inheritance:
- Usually recessive.
Dose effect:
- As long as ~ >10% of enzyme activity is retained, the disease won’t manifest.
Phenotype correlation:
- Complete loss of fn = more severe.
- Residual but reduced fn (hypomorphic) = milder.
Which chromosomes does autosomal inheritance affect, and can this inheritance be transmitted between males
Chromosomes:
- Chromosomes 1 - 22
- Pseudoautosomal regions of X / Y.
Male-Male transmission:
- Yes.
What chromosome does X-linked inheritance affect, and can this inheritance be transmitted between males
Chromosome:
- Most of chromosome X.
Male-Male transmission:
- No.
Autosomal Dominant:
- What is autosomal dominant inheritance
- What is the chance of transmission to offspring.
- Can transmission between males occur.
- What is the difference between inherited vs de novo
- What are some special features of this
What it is:
- Heterozygous.
- Change in ONE allele only required to cause trait / condition.
- At least one parent of an affected individual is affected.
- Affects both males and females equally.
Offspring risk:
- 50%.
Male-Male transmission:
- Yes.
Inheritance vs de novo:
- Inherited - when condition does not limit reproductive potential.
- de novo - when condition does limit reproductive potential.
Special features:
- Phenotype can be varied due to penetrance and expressivity.
- Age at onset of disease may be delayed (e.g. Huntington’s).
Autosomal Dominant Examples (divided into body system and de novo).
Nervous system:
- Huntington.
- Neurofibromatosis.
- Myotonic dystrophy.
- Tuberous sclerosis.
Urinary:
- Polycystic kidney disease.
GI:
- Familial polyposis coli.
Haematopoietic:
- Hereditary spherocytosis.
- vWD.
Skeletal:
- Marfan.
- Ehlers-Danlos (some variants).
- Osteogenesis imperfecta.
- Achondroplasia.
Metabolic:
- Familial hypercholesterolaemia.
- Acute intermittent porphyria.
de novo:
- Cornelia de Lange syndrome (NIPBL).
- Rubenstein Taybi syndrome (CREBBP)
What is Incomplete Penetrance and what are some examples.
- Occurs in Autosomal dominant conditions
- When you have the mutated gene but do not express the phenotype.
Examples:
- Breast cancer BRCA1 / 2 –> requires 2 hits to get cancer.
- Neurodegenerative disorders.
What is Variable Expressivity and what are some examples.
- Occurs in Autosomal dominant conditions
- When you have the mutated gene, and express the phenotype but each person has a different variation of the phenotype.
Examples:
- Neurofibromatosis 1
- Noonan.
- Stickler.
- Tuberous sclerosis.
- Myotonic dystrophy.
What is Mosaicism and what are some examples
What is it:
- Parent has a somatic variant in some of their cell lines.
- If variant present in gonads –> transmitted to offspring in ALL of their cells.
Example:
- Neurofibromatosis type 1.
- Epileptic encephalopathy.
Autosomal Recessive:
- What is autosomal recessive inheritance
- What is the chance of transmission to offspring
- What are special characteristics / features of this
What it is:
- Change on BOTH alleles required to cause a trait / condition.
- Usually results in loss of function.
- Parents of affected individual are not usually affected but siblings may show disease.
Offspring risk:
* 25%.
Special characteristics / features:
- Individuals with change on just ONE allele = Carrier.
- Sibling risk of carriage = 2 / 3.
- Consanguity can reveal disease.
- More uniform expression compared with autosomomal dominant.
- Onset is early in life.
What is Pseudodominance and what are some examples
What it is:
- Apparent dominant inheritance pattern in a recessive condition.
- Seen where carriers are common OR consanguineous pedigrees.
Examples:
- Haemochromatosis.
X-linked inheritance:
-What is X-linked inheritance
-What gender is usually affected.
-What are special characteristics / features of this
What it is:
- Transmission of traits / conditions by X-Chromosome.
- Usually recessive
Gender most affected:
- Males.
Special characteristics / features:
- Females may not be true “carriers” - i.e. express full or partial disease, depending on what allele is inactivated and how much is inactivated through X-inactivation.
- Males are hemizygous (i.e. only have one X-chromosome for mutation to be expressed).
- Males transmit to ALL daughters and NO sons.
- Females transmit to HALF sons AND daughters (but daughters can be affected or carriers).
- NO male to male transmission.
