clinical genetics 2 Flashcards
What is the most common type of genomic variation?
Substitution of one nucleotide for another
What causes nucleotide substitutions?
Misincorporation of a nucleotide during DNA synthesis or chemical modification of the base
Define synonymous substitution
Resulting in a change in the codon without altering the amino acid
What is a non-synonymous substitution also known as?
Missense variant
What does a non-synonymous substitution result in?
A change in the codon and the encoded amino acid
What is a stop gain variant also referred to as?
Nonsense variant
What does a stop gain variant introduce?
A premature stop codon resulting in truncation of the protein
What is splicing in the context of genomic variation?
Disruption of normal splicing, often occurring at the junctions between an intron and an exon
What is an insertion/deletion (indel) variant?
One or more nucleotides may be inserted or lost in a DNA sequence
What happens if an indel affects one or two nucleotides within the ORF of a protein-coding gene?
It can result in a frameshift variant, disrupting the amino acid sequence
What are simple tandem repeat variants?
Variations in the length of simple tandem repeats of DNA, arising from slippage during meiosis
What are microsatellite and minisatellite repeats?
Microsatellites are small repeats; minisatellites are larger repeats
What is the relationship between the size of repeats and their stability?
Longer repeats tend to be more unstable
What are copy number variations?
Variation in the number of copies of an individual segment of the genome from the usual diploid content
What is trisomy?
The gain of a whole chromosome
What is monosomy?
The loss of a whole chromosome
What is Turner syndrome?
Monosomy for the X chromosome, affecting approximately 1 in 2500 live births
What are the two processes that can lead to structural chromosomal anomalies?
- Non-homologous end-joining
- Non-allelic homologous recombination
What happens during non-homologous end-joining?
Segments of DNA that are not normally contiguous are joined
What are microdeletions and microduplications?
Anomalies too small to be detected by microscopy
What factors influence the consequence of a genomic variant?
- Variant type
- Nature of the gene product
- Position of the variant in the protein
What are neutral variants?
Variants that have no effect on quality or type of protein produced
What are loss-of-function variants?
Variants resulting in loss or reduction in normal protein function
What are gain-of-function variants?
Variants that result in a gain of protein function
What are dominant negative variants?
Heterozygous changes that produce an abnormal protein interfering with normal protein function
How many variants do we have in our genome?
3–5 million variants occurring approximately every 300 bases
What is a single nucleotide polymorphism (SNP)?
A substitution of a single base
What role do genome-wide association studies (GWAS) play?
Identifying protective and detrimental polymorphisms associated with common disease
What is the significance of the SLC2A9 gene polymorphism?
It explains variation in serum urate concentration and predisposes to gout
What is the relationship between genetic variants and evolutionary selection?
Advantageous variants improve reproductive fitness; deleterious variants are excluded through evolution
What is familial genetic disease?
Disease caused by constitutional variants inherited through the germ line
What is a family tree or pedigree?
A tool used by clinical geneticists to take a three-generation family history
What information is typically gathered in a pedigree?
- Medical conditions in family members
- Consanguinity
- Dates of birth and death
- History of pregnancy loss or infant death
what is somaic genetic disease?
Somatic variants are not inherited but instead occur during post-zygotic mitotic cell divisions at any point from embryonic development to late adult life.
The most important example of human disease caused by somatic variants is cancer
AD ineritance pattern ?
The offspring risk for an individual affected with an autosomal dominant condition is 1 in 2 (or 50%).
AR inheritance pattern?
Approximately 1 in 4 children born to carriers of an autosomal recessive condition will be affected. The offspring risk for carrier parents is therefore 25% and the chances of an unaffected child, with an affected sibling, being a carrier is 2/3.
X-linked recessive inheritance?
- predomonantly affects male who carry the mutant allele (this is because males only have one chromosome)
- The gene can be transmitted from female carriers to their sons: in families with an X-linked recessive condition, there are often a number of affected males related through unaffected females.
Occasionally, female carriers may exhibit signs of an X-linked disease due to a phenomenon called skewed X-inactivation. All female embryos, at about 100 cells in size, stably inactivate one of their two X chromosomes in each cell. Where this inactivation is random, approximately 50% of the cells will express the genes from one X chromosome and 50% of cells will express genes from the other. Where there is a mutant gene, there is often skewing away from the associated X chromosome, resulting in an unaffected female carrier. However, if, by chance, there is a disproportionate inactivation of the normal X chromosome with skewing towards the mutant allele, then an affected female carrier may be affected (albeit more mildly than males).
Inheritance of mitochondiral diseases?
The inheritance of mtDNA disorders is characterised by transmission from females, but males and females generally are equally affected
What is imprinting?
Several chromosomal regions (loci) have been identified where gene expression is inherited in a parent-of-origin-specific manner; these are called imprinted loci. Within these loci the paternally inherited gene may be active while the maternally inherited may be silenced, or vice versa. Variants within imprinted loci lead to an unusual pattern of inheritance where the phenotype is manifest only if inherited from the parent who contributes the transcriptionally active allele.
