18.03.01 Genetic Definitions

Question 1

Define ‘anticipation’

Answer 1

Phenomenon in which the signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. Anticipation typically occurs with disorders that are caused by a trinucleotide repeat expansion, these dynamic mutations are unstable and tend to expand on transmission to the next generation

Question 2

Give some examples of disorders which show anticipation

Answer 2

Fragile XMyotonic Dystophy 1DRPLAHuntington diseaseSCA1SCA3SCA7

Question 3

What type of TNR does not show anticipation? Why?

Answer 3

Anticipation is not observed in polyalanine-mediated disorders encoded by imperfect repeat (GCN)n. This repeat is more stable than CAG/CTG repeats and less prone to replication slippage.

Question 4

Define ‘age-related mosaicism’

Answer 4

The accumulation of somatic/germline mutations over the course of a person’s life resulting in mosaicism. Normal part of ageing considering number of cells dividing and mutation rate of DNA.

Question 5

Define ‘variable expressivity’

Answer 5

Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype

Question 6

Give some examples of disorders which show variable expression

Answer 6

Many different disorder!Marfan syndrome NF1

Question 7

Define ‘penetrance’

Answer 7

• Penetrance represents the proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms

Question 8

What is the likely cause(s) of reduced penetrance?

Answer 8

Combination of (largely unknown) factors from:geneticsenvironmental lifestyle

Question 9

What factor is important to know ahead of determining the penetrance of an allele?

Answer 9

Consensus definition what constitutes the presence of a phenotype is essential - HFE example

Question 10

What is the ‘attributable risk’ of an allele?

Answer 10

• Attributable risk is that proportion of total risk that can be attributed to the presence of the allele. For alleles with incomplete penetrance, the penetrance of the allele is not the same as the attributable risk. For example, many alleles have been shown, through association studies, to cause some form of cancer, often with low penetrance, but cases of the cancer would arise even without the presence of the allele.

Question 11

What are sex-limiting genes?

Answer 11

Sex-limited genes are genes which are present in both sexes but expressed only in one sex, causes the two sexes to show different traits or phenotypes. Examples: lactation in females and beard growth in males

Question 12

Give some examples of sex-limiting genes.

Answer 12

Male Precocious Puberty is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. Affected males generally exhibit signs of constitutive activativation of a LH receptor leading to puberty by age 4 years. Caused by dominant gain-of-function mutations in LHCGR (2p16.3) causing autonomous Leydig cell activity and very early puberty in males only.BPES (blepharophimosis, ptosis, and epicanthus inversus syndrome) (3q22.3). Type I (females) = blepharophimosis, ptosis, and epicanthus inversus and premature ovarian failure. Type I (males) = blepharophimosis, ptosis, and epicanthus inversus. Caused by polyalanine expansion in FOXL2: transcription factor selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it’s predominantly expressed in the ovary.

Question 13

Define ‘epistasis’.

Answer 13

Is a form of interaction between nonallelic genes in which one combination of such genes has a dominant effect over other combinations.In cases where direct masking of expression occurs, the locus whose expression is masked is described as hypostatic, and the locus whose alleles cause the masking is described as epistatic.Epistasis can occur directly at the genomic level, where one gene could code for a protein

Question 14

Define ‘pleiotropy’.

Answer 14

Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. The underlying mechanism is that the gene codes for a product that is, for example, used by various cells, or has a signaling function on various targets. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously

Question 15

Give an example of a genetic disease which demonstrated pleiotropy.

Answer 15

AlbinismSickle-cell anaemiaPKU (PAH mutations)

Question 16

What is an amorphic mutation?

Answer 16

describes a mutation that causes complete loss of gene function. Amorph is sometimes used interchangeably with “genetic null”. An amorphic mutation might cause complete loss of protein function by disrupting translation (“protein null”) and/or preventing transcription (“RNA null”). An amorphic allele elicits the same phenotype when homozygous and when heterozygous to a chromosomal deletion or deficiency that disrupts the same gene

Question 17

What is a hypomorphic mutation?

Answer 17

describes a mutation that causes a partial loss of gene function. A hypomorph is a reduction in gene function through reduced (protein, RNA) expression or reduced functional performance, but not a complete loss. The phenotype of a hypomorph is more severe in trans to a deletion allele than when homozygous. Hypomorphs are usually recessive, but occasional alleles are dominant due to haploinsufficiency.Example: Friedreich’s ataxia – majority of cases caused by homozygosity for GAA repeat expansion in exon 1 of frataxin which causes reduced expression. Some cases are caused by compound heterozygosity for GAA expansion and an inactivating point mutation. Homozygosity for inactivating mutations is embryonic lethal.

Question 18

What is an hypermorphic mutation?

Answer 18

a type of mutation in which the altered gene product possesses an increased level of activity. A hypermorphic mutation causes an increase in normal gene function. Hypermorphic alleles are gain of function alleles. A hypermorph can result from an increase in gene dose (a gene duplication), from increased mRNA or protein expression, or constitutive protein activity.

Question 19

What is an antimorph mutation?

Answer 19

are dominant mutations that act in opposition to normal gene activity. Antimorphs are also called dominant negative mutations. Increasing wildtype gene function reduces the phenotypic severity of an antimorph, so the phenotype of an antimorph is worse when heterozygous than when in trans to a gene duplication.

Question 20

What is a neomorphic mutation?

Answer 20

Neomorphic mutation causes a dominant gain of gene function that is different from the normal function. A neomorphic mutation can cause ectopic mRNA or protein expression, or new protein functions from altered protein structure. Changing wildtype gene dose has no effect on the phenotype of a neomorph.

Question 21

Define ‘hemizygous’.

Answer 21

a state of having a gene with no counterpart allele in a diploid cell. E.g. men are normally hemizygous for genes on the X chromosome.

Question 22

Define ‘ compound heterozygous’

Answer 22

The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair. These 2 mutations are different and not identical to each other

Question 23

Define ‘haploinsuffiency’

Answer 23

: A situation in which half amount of a gene product is not enough to maintain normal function for instance, individual with heterozygous mutation or hemizygous at a particular locus is clinically affected.