20.03.01 Patterns of inheritance - Definitions

Question 1

What is anticipation

Answer 1

The phenomenon in which the symptoms become more severe and start earlier in successive generations. Seen in repeat disorders (Fragile X, DM1, HD).

Question 2

Does repeat length fully correlate with onset and severity

Answer 2

-Yes to a degree. -The larger the expansion the earlier the onset and more severe the symptoms -The longer the repeat the more unstable and more prone to expanding further -However there is variability between affected individuals (even those within the same family) suggesting other factors are involved (lifestyle/ environment/ somatic instability)

Question 3

What effect does somatic instability have in repeat disorders

Answer 3

-Can modify the age of onset/ disease severity. Cause further expansion.

Question 4

What can stabilise repeat expansions

Answer 4

Interruptions

Question 5

What are intermediate repeat alleles

Answer 5

Alleles that wouldn’t cause disease in patient or children but may show instability in future generations (especially if uninterrupted).

Question 6

What are premutation repeat alleles

Answer 6

Pure repeats that are not pathogenic (expect FXTAS/ FXPOI), but are prone to further expansion in the next generation

Question 7

Mechanism of expansion

Answer 7

Polymerase slippage. Slipped strands mispair causingformation of secondary structures (hair pin loops). Secondary strucutres cause replication fork blockage, spliappage of lagging strand, misprocessing of Okazaki fragments and unequal crossing over. Alleles mispair during meotic crossing-over, resulting one expanded and one contracted tract.

Question 8

Which repeat disorders show maternal anticipation (expansion when inherited from mother)

Answer 8

Fragile X, DM1

Question 9

Which repeat disorders show paternal anticipation (expansion when inherited from father)

Answer 9

DRPLA, HD, SCA1, 3, 17

Question 10

What is the mechanism behind paternal anticipation

Answer 10

CAG repeats are unstable during spermatogenesis.

Question 11

What is ascertainment bias

Answer 11

A term in population genetics that describes systematic deviations from the expected theoretical result attributable to the sampling processes.

Question 12

What three main biases give false impression of anticipation

Answer 12

• Preferential ascertainment of parents with late onset disease, since earlier onset would have caused reduced fertility
• Preferential ascertainment, due to severity, of those in childhood with early onset
• Preferential ascertainment of parent-child pairs with simulatenous onset.

Question 13

Examples of anticipation in cancer

Answer 13

-Anticipation associated with decreased telomere length in BRCA families but not sporadic cases.

Question 14

What is age-related mosaicism

Answer 14

-Accumulation of somatic/germline mutations over the course of a person’s life, resulting in mosaicism.

Question 15

Examples of age related mosaicism

Answer 15

• Somatic aneuplodies in older people. May reflect normal age-related anaphase lag
• Could be a passive consequence or agent of agent (hypertension, stherosclerosis, cancer(
• Cancer. Accumulation of somatic variants as we age, which can enhance cell proliferation or genomic instability. Could be due to decline in efficiency of DNA repair mechanisms with age.

Question 16

What is variable expressivity

Answer 16

-When a phenotype is expressed to a different degree among individuals with the same genotype.

Question 17

Examples of variable expressivity

Answer 17

• Marfan syndrome.
  
  • Individuals have FBN1 variants but some can have very mild symptoms (tall and thin, with long slender fingers)
  • Others have severe life threatening complications with heart and blood vessels.
• Neurofibromatosis type 1. Due to NF1 mutations
  
  • Mild= cafe au lait
  • Severe= dermal neurofibromas
• Complicates counselling as finding a mutation does not mean we can predict how severely they will be affected

Question 18

What is disease penetrance

Answer 18

Penetrance is the proportion of individuals carrying a particular variant that also expressess an associated trait.

Question 19

What is complete penetrance

Answer 19

All individuals who have the mutation will have clinical symptoms of disease.

Question 20

What is reduced penetrance

Answer 20

Where clinical symtpoms are not always present in people who have the disease-causing variant.

Question 21

Example of reduced penetrance

Answer 21

• DYT1 (early onset primary dystonia)
  
  • 99% individuals have a three base pair deletion of TOR1A gene c.907_909delGAG.
  • Penetrance is 30%
  • 30% of people who inherit the variant will develop symptoms.

Question 22

What is attributable risk

Answer 22

Proportion of total risk that can be attributed to the presence of the allele.

Question 23

What are polygenic traits

Answer 23

Biological traits that are influenced by many genes as well as environmental conditions and epigenetic expression.

Question 24

What are sex limited genes

Answer 24

Genes that are present in both sexes but expressed only in one sex and causes the two sexes to show different traits or phenotypes.

Question 25

Examples of sex-limited diseases

Answer 25

• Familial precocious puberty. Gondaotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern
• Males exhibit signs of puberty at age 4.
• Gain of function mutations in LHCGR gene (luteinizing hormone receptor gene)
• Mutations cause a constitutively active LH receptor leading to autonomous Leydig cell activity and very early puberty in males only

Question 26

What is epistasis

Answer 26

Interaction of non-allelic genes, which in one combination has a dominant effect over other combinations.

Question 27

Example of epistasis

Answer 27

• Bombay phenotype results in O type blood, who are homozygous for h allele.
• H mutation blocks addition to fucose molecule to the H antigen precursor. Since A and B antigens are converted from H antigen, their formation is also blocked in individuals who carry the IA and IB alleles.

Question 28

What is the difference between hypostatic and epistatic

Answer 28

• In cases where direct masking of expression occurs
  
  • Hypostatic= the locus whose expression is masked
  • Epistatic= the locus whose alleles cause the masking

Question 29

What is pleiotropy

Answer 29

• Pleiotropy is when one gene influences two or more seemingly unrelated phenotypic traits.
• Often occurs when a gene encodes a protein that is used by various cells or has various targets

Question 30

Example of pleiotropy

Answer 30

• Phenylketonuria (PKU)
• Mental retardation, reduced hair and skin pigmentation
• Mutations in PAH gene, which encodes enzyme phenylalanine hydroxylase
• Enzyme converts phenylalanine to tyrosine
• Depending on the mutation the activity of PAH is reduced or entirely abolished.
• Unconverted phenylalanine builds up in circulation, which is toxic to the developing nervous system.
• Tyrosine is used to make melanin, hence less pigmentation in affected children.
• Treatment is low phenylalanine diet

Question 31

What is an amorphic mutation

Answer 31

A mutation that causes complete loss of gene function (null).

Question 32

What is a hypomorphic mutation

Answer 32

A mutation that causes a partial loss of gene function

Question 33

What is a hypermorphic mutation

Answer 33

A mutation that causes the altered gene product to have increased activity or increased dose (duplication)

Question 34

What is an antimorph

Answer 34

A dominant mutation that acts in opposition to normal gene activity (dominant negative)

Increasing wildtype gene dose (duplication) would reduce severity of an antimorph.

Question 35

What is a neomorphic mutation

Answer 35

Causes a dominant gain of function different from normal function.

• Ectopic mRNA or protein expression
• New protein functions from altered protein structure

Changing wild type gene dose will have no effect

Question 36

Give an example of a hypomorph

Answer 36

• Friedreich ataxia
• Caused by homozygosity of GAA expansion in FXN gene or compound het expansion and inactivating point mutation.

Question 37

What is hemizygous

Answer 37

• State of having a gene with no counterpart allele in a diploid cell.
• Men are hemizygous for genes on X chromosome

Question 38

What is compound heterozygous

Answer 38

Presence of two different mutant alleles at a particular locus, one on each chromsome of a pair. Not identical (if they were then this would be homozygous)

Question 39

What is haploinsufficiency

Answer 39

A situation where half the amount of gene product is not enough to maintain normal function

Question 40

What is linkage disequilibrium

Answer 40

Phenomenon where there is non-random association of alleles at two or more loci.

I.e. variants co-occur together in an allele more than would be expected if a random distribution of variants was occurring.

e.g. F508del is cis with 9T in CFTR (98% of alleles).