Genetic screening Flashcards
(25 cards)
What are the 2 main types of genetic variation?
- Structural
- Copy number (deletions & duplications)
- positional (insertions, translocations)
- orientational (inversions) - Sequence level
- single base substitutions
- small deletions/duplications
- repetitive sequence
Why do we perform genetic tests, and what samples does it entail?
Aim of detecting genetic alterations associated with disease. Samples include DNA and RNA (direct) or chromosomes, proteins or metabolites (biochemical or immunohistochemical test)
Define Cytogenetics
Studies the structure, properties and behaviour of chromosomes
Define Molecular genetics, what tests does it generally entail?
Studies the structure and function of genes at a molecular level. Tests typically DNA or RNA based
What does Cytogenetics combined with Molecular genetics mean?
That the line between both is blurring - molecular methods can detect cytogenetic abnormalities
Can small and large variants be disease causing or not?
Small and large variants may be disease causing or not.
Can repetitive elements be disease causing or not?
Repetitive elements such as tandems or interspersed are non disease-causing but may predispose to rearrangements or expansions/contractions
What are the causes of genetic variation?
- DNA repair mechanisms
- DNA replication errors (proof-reading or fork stalling)
- Homologous DNA recombination during meiosis
- retrotransposition
What is the significance of molecular diagnosis?
- accurate diagnosis
- possible prognosis
- better informed genetic counseling
- prenatal, pre-implantation, pre-symptomatic diagnosis
- appropriate trial treatment/enrolment
- drug interactions
What are the consequences of genetic variation?
- no change in phenotype
- alternative phenotypes of no medical consequence
- disease susceptibility
- pathogenic
What are some databases of variation?
- “Normal” variation
- ExAC, gnomAD, Exome Variant Server, 1000 genomes, dbSNP
- disease associated variation
- DECIPHER and Human Gene Mutation Data (HGMD)
Why does caution need to be taken when calling variation “normal” vs “abnormal”?
As variation occurs between population.
Common variant = “normal” e.g. BRCA2 (not all people with this get breast cancer)
Rare variant = “abnormal”
e.g. Dmd (nonsense mutation)
How are DNA sequence changes described?
- with reference to the current versions of the genome
- using the approved gene name
- using internationally recognised nomenclature
- change at the DNA coding level (c)
- change at the amino acid or protein level (p)
Why do we need to describe sequence changes in particular ways?
- no of gene landmarks can change
- reference seq and genome are updated regularly
- gene names can change
Therefore, variants can be recognised across laboratories/countries over time
Define polymorphism
A variant that is common and normal in population (>1%), therefore presumed benign. Ancient with weak or no effect.
Define autosomal dominant
Where the disease gene is on an autosome. At least one individual in each successive generation is affected (exception of incomplete penetrance). Independent of sex.
One copy (het) of the disease allele = disease phenotype - normal allele cannot fully compensate.
Two copies = usually lethal (or more severe).
What’s an example of autosomal dominant
Examples include Neurofibromatosis 1 and 2 (NF1 and NF2): growth of tumours (usually non-cancerous) in the NS.
NF1 prevalence 1:35000
NF2 prevalence 1:25000 (risk of early death)
Define autosomal recessive
One copy = no phenotype or very mild.
Two copies (hom or compound het) of the disease allele = disease phenotype.
Horizontal transmission (may have affected siblings, but usually not affected earlier generations) - parents usually carriers.
Incidence independent of sex (25% of disease/not getting and 50% carrier)
What’s an example of autosomal recessive disease?
What drug has been approved for it?
Spinal muscular atrophy (SMA): progressive muscle wasting disease with loss of motor neurons. Most common cause of infant death (different age onset). Caused by mutations in SMN1 gene
Nusinersen first drug approved for use of SMA.
What is an X-linked dominant disease?
Disease gene is on the X chromosome. Males typically more severely affected. Higher prevalence in females as more chance of inheriting an X-linked mutation.
One copy (het/hemizygous) of the disease allele = disease phenotype.
All daughters of affected father will be affected, none of their sons (unless mother also affected).
If mother affected, 50% of her children will be affected.
What are the 2 examples of X-linked dominant disease?
Rett syndrome and Fragile X syndrome.
Rett syndrome: neurological disorder of the brain’s grey matter –> deceleration of head growth rate, small hands and feet. Nearly all females. Caused by mutation in MECP2 gene.
Fragile X: intellectual disability, various physical characteristics. Most common single gene cause of autism. Caused by expansions of CGG triplet repeat region in the 5’UTR of the FMR1 gene. Boys usually more affected.
What is X-linked recessive disease?
Hemizygous males affected (can be lethal).
For females: 2 copies of disease allele = disease phenotype. 1 copy = no or mild phenotype.
In mothers, 50% chance of sons having disease, 50% of daughters being carriers.
In males, no sons affected. All daughters carriers.
What is an example an X-linked recessive disease?
Duchenne muscular dystrophy: progressive skeletal muscle degeneration. Onset = early childhood, survival until early thirties. Affects 1 in 3500 males. Cause: mutations in the dystrophy gene (DMD) –> absence of dystrophin protein
What is mitochondrial inheritance?
What do mitochondrial diseases usually affect?
Typically, maternal inheritance where 99.9% of mtDNA is inherited from mother.
Mother passes on disease to all children, father never passes on disease.
Diseases usually affect muscle, nerve and eye
