Principles of Genetic disease

Question 1

What are frameshift mutations?

Answer 1

Occurs when nucleotides are added or subtracted in non-multiples of three

Results in subsequent codons specifying the wrong amino acid or termination signal

Question 2

What is Waardenburg syndrome?

Answer 2

Truncation, splicing abnormalities and inactivation of the DNA binding region

Autosomal dominant

Pigmentary disturbance, wide nasal bridge and cochlear deafness

Question 3

What is Huntington disease caused by?

Answer 3

Tandem repeat expansion

Question 4

What are some possible mutations in regulation and RNA processing?

Answer 4

Promoter mutations

Splicing mutations

Mutations in transcription factors

Transposons

Tandem repeat expansion

Question 5

What is Loss-of-function?

Answer 5

A change in a gene negatively affecting the amount or function of a gene product

Question 6

What is haploinsufficiency?

Answer 6

50% of the normal gene product is not sufficient for normal function

Usually caused by loss of function mutations

Question 7

What is gain-of-function?

Answer 7

A change in a gene, resulting in a gene product that is usually biologically harmful

Most commonly, overexpression or inappropriate expression.

Question 8

What does it mean to be Dominant negative?

Answer 8

When a defective protein is not only nonfunctional but it inhibits function of normal counterparts

E.g. Osteogenesis imperfecta

Question 9

What is a mutation?

Answer 9

any permanent change in the nucleotide sequence of a genome

Question 10

What is a polymorphism?

Answer 10

A mutation that is relatively abundant in a population.

Many are silent mutations

E.g. Rh +/-

Question 11

What is a silent mutation?

Answer 11

A gene mutation that has no consequence at the phenotypic level

Functionally equivalent AAs, and redundancy in the genetic code are responsible for these

I.e. protein product of this mutation functions just as well

Question 12

What is Dosage sensitivity

Answer 12

The level of protein product produced by a gene can produce different phenotypes at various levels, rather than one phenotype in the presence and one in the absence of a protein.

E.g. different types of Charcot-Marie-Tooth disease

Question 13

What is Charcot-Marie-Tooth disease?

Answer 13

Demyelination is the hallmark

Loss of PNS motor and sensory neurons

Many phenotypes depending on mutation

Question 14

What causes CMT Disease Type 1A?

Answer 14

Duplications in PMP22

Autosomal dominant

Question 15

What causes hereditary neuropathy with liability to pressure palsies (HNPP) or CMT1B?

Answer 15

Deletions in PMP22

Affected nerves have focal regions with tomaculous changes or sausage shaped figures

Less severe phenotype than CMT

Autosomal dominant

Question 16

What causes Dejerine-Sottas syndrome (DSS) or CMT3?

Answer 16

Point mutations in PMP22

Autosomal recessive

Clinically similar to CMT, but less severe and occurs in infancy

Question 17

What is a germline mutation?

Answer 17

A mutation that occurs in every cell in an individual and that was therefore inherited from a parent

Question 18

What is a somatic mutation?

Answer 18

A mutation occurring only in a subset of somatic cells

Question 19

What does the phenotype of a somatic mutation depend on?

Answer 19

Which cells and tissues are affected

Nature of the gene product

Question 20

What is allelic heterogeneity?

Answer 20

the occurence of more than one disease causing allele at a locus

E.g. mitochondrial depletion syndromes, CMT

Question 21

What is locus heterogeneity?

Answer 21

The association of more than one locus with a specific clinical phenotype

E.g. hearing loss where it is common for two affected people to produce normal children

Question 22

What is Clinical heterogeneity?

Answer 22

Variability in relation to presentation or treatment of a disease

Question 23

What are modifier genes?

Answer 23

genes that affect the occurrence or severity of a phenotype associated with mutations in a non-allelic gene

Question 24

What is an epiallele?

Answer 24

Alleles of genes containing epigenetic marks

Question 25

What is gene silencing?

Answer 25

Inactivation of a gene

Question 26

What is imprinting?

Answer 26

determination of the expression of a gene by its parental origin

sub-type of gene silencing

Question 27

What is Angelman Syndrome?

Answer 27

Unusual facial appearance, short stature, spasticity, seizures

Caused by maternal inheritancy of 15 deletions

Paternal is imprinted

Question 28

What is Prader-Willi Syndrome?

Answer 28

Obesity, small hands and feet, short stature, hypogonadism

Paternal inheritance of 15 deletions

Mother is imprinted