clinical genetics 2

Question 2

What is the most common type of genomic variation?

Answer 2

Substitution of one nucleotide for another

Question 3

What causes nucleotide substitutions?

Answer 3

Misincorporation of a nucleotide during DNA synthesis or chemical modification of the base

Question 4

Define synonymous substitution

Answer 4

Resulting in a change in the codon without altering the amino acid

Question 5

What is a non-synonymous substitution also known as?

Answer 5

Missense variant

Question 6

What does a non-synonymous substitution result in?

Answer 6

A change in the codon and the encoded amino acid

Question 7

What is a stop gain variant also referred to as?

Answer 7

Nonsense variant

Question 8

What does a stop gain variant introduce?

Answer 8

A premature stop codon resulting in truncation of the protein

Question 9

What is splicing in the context of genomic variation?

Answer 9

Disruption of normal splicing, often occurring at the junctions between an intron and an exon

Question 10

What is an insertion/deletion (indel) variant?

Answer 10

One or more nucleotides may be inserted or lost in a DNA sequence

Question 11

What happens if an indel affects one or two nucleotides within the ORF of a protein-coding gene?

Answer 11

It can result in a frameshift variant, disrupting the amino acid sequence

Question 12

What are simple tandem repeat variants?

Answer 12

Variations in the length of simple tandem repeats of DNA, arising from slippage during meiosis

Question 13

What are microsatellite and minisatellite repeats?

Answer 13

Microsatellites are small repeats; minisatellites are larger repeats

Question 14

What is the relationship between the size of repeats and their stability?

Answer 14

Longer repeats tend to be more unstable

Question 15

What are copy number variations?

Answer 15

Variation in the number of copies of an individual segment of the genome from the usual diploid content

Question 16

What is trisomy?

Answer 16

The gain of a whole chromosome

Question 17

What is monosomy?

Answer 17

The loss of a whole chromosome

Question 18

What is Turner syndrome?

Answer 18

Monosomy for the X chromosome, affecting approximately 1 in 2500 live births

Question 19

What are the two processes that can lead to structural chromosomal anomalies?

Answer 19

• Non-homologous end-joining
• Non-allelic homologous recombination

Question 20

What happens during non-homologous end-joining?

Answer 20

Segments of DNA that are not normally contiguous are joined

Question 21

What are microdeletions and microduplications?

Answer 21

Anomalies too small to be detected by microscopy

Question 22

What factors influence the consequence of a genomic variant?

Answer 22

• Variant type
• Nature of the gene product
• Position of the variant in the protein

Question 23

What are neutral variants?

Answer 23

Variants that have no effect on quality or type of protein produced

Question 24

What are loss-of-function variants?

Answer 24

Variants resulting in loss or reduction in normal protein function

Question 25

What are gain-of-function variants?

Answer 25

Variants that result in a gain of protein function

Question 26

What are dominant negative variants?

Answer 26

Heterozygous changes that produce an abnormal protein interfering with normal protein function

Question 27

How many variants do we have in our genome?

Answer 27

3–5 million variants occurring approximately every 300 bases

Question 28

What is a single nucleotide polymorphism (SNP)?

Answer 28

A substitution of a single base

Question 29

What role do genome-wide association studies (GWAS) play?

Answer 29

Identifying protective and detrimental polymorphisms associated with common disease

Question 30

What is the significance of the SLC2A9 gene polymorphism?

Answer 30

It explains variation in serum urate concentration and predisposes to gout

Question 31

What is the relationship between genetic variants and evolutionary selection?

Answer 31

Advantageous variants improve reproductive fitness; deleterious variants are excluded through evolution

Question 32

What is familial genetic disease?

Answer 32

Disease caused by constitutional variants inherited through the germ line

Question 33

What is a family tree or pedigree?

Answer 33

A tool used by clinical geneticists to take a three-generation family history

Question 34

What information is typically gathered in a pedigree?

Answer 34

* Medical conditions in family members * Consanguinity * Dates of birth and death * History of pregnancy loss or infant death

Question 35

what is somaic genetic disease?

Answer 35

Somatic variants are not inherited but instead occur during post-zygotic mitotic cell divisions at any point from embryonic development to late adult life. ## Footnote The most important example of human disease caused by somatic variants is cancer

Question 36

AD ineritance pattern ?

Answer 36

The offspring risk for an individual affected with an autosomal dominant condition is 1 in 2 (or 50%).

Question 37

AR inheritance pattern?

Answer 37

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.

Question 38

X-linked recessive inheritance?

Answer 38

- 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. ## Footnote 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).

Question 39

Inheritance of mitochondiral diseases?

Answer 39

The inheritance of mtDNA disorders is characterised by transmission from females, but males and females generally are equally affected

Question 40

What is imprinting?

Answer 40

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.