genetics 1

Question 1

What is a mutation?

Answer 1

A change or variation in the base pair sequence of DNA
New mutations may arise in the somatic cells or germline these can be positive, neutral, damaging or lethal
Germinal mutations can be transmitted to the offspring
Variations in the DNA sequences occurs rarely as a resultof new mutation
The majority of mutations are inherited

Question 2

What is the purpose of mutations and why do we get them?

Answer 2

They generate genetic diversity where there is about 10 million differences between maternal and paternal chromosomes
If a mutation is advantageous natural selection provides a selection pressure
Endogenous mutations are due to errors in replication and repair
Mutagens increase the frequency of mutations

Question 3

What are the types of mutations?

Answer 3

Chromosomal abnormalities
Single gene defects- monogenic disorders
Complex/multifactorial disease

Question 4

What are monogenic/single gene disorders?

Answer 4

These are caused by individual mutant genes
May be hetero or homozygous
May be nuclear or mitochondrial
Usually exhibit an obvious inheritance pattern
They are individually rare but collectively responsible for a significant proportion of disease and death (2%)

Question 5

What are chromosomal disorders?

Answer 5

Whole chromosomes or chromosome segments are affected
These are rare affecting 7/1000 liveborn infants but do account for more than 50% of all spontaneous first trimester miscarriages due to things such as trisome 16 which is the most common trisomy but embryonic lethal
The most common live births are trisome 21, 18 and 13

Question 6

What are the different types of chromosomal abnormalities?

Answer 6

Moasaicism
Numerical abnormalities (including monosomies and trisomies)
Structural abnormalities (including deletions and duplications such as Pallister Killian Syndrome)

Question 7

What is trisomy 18?

Answer 7

This is Edwards syndrome which affects 1 in 3000 to 1 in 5000 and is frequently miscarried or still born
The median life expectancy is 4 days with only 5-10% of individuals being expected to survive beyond the 1 year mark though mosaics may survive into adulthood
This affects three times more females than males
90% of cases can be picked up at 20 weeks ultrasound scan

Question 8

What are the clinical features of trisome 18?

Answer 8

A small abnormally shaped head
A small jaw and mouth
Long fingers that overlap in a clenched fist
Heart and kidney problems
Difficulties in feeding
Frequent infections
Severe learning difficulties

Question 9

What is Pallister killan syndrome?

Answer 9

This is caused by a duplication on chromosome 12 with there only being 200 cases world wide which could be due to the condition being underdiagnosed

Question 10

What are the clinical features of Paillister killian syndrome?

Answer 10

Sparse hair pattern
Coares face with high forehead
Widely spaced eyes
Diaphragmatic hernia
Reduced muscle tone (floppy)
Skin lacking in pigmentation
Seizures
Learning difficulties
Shortened life span

Question 11

What are the consequences of a chromosome break?

Answer 11

If there is only one break on one chromosome then there may be a terminal deletion
If there are two breaks in one chromosome then there may be inversions, ring chromosomes or interstitial deletions

Question 12

What are the syndromes associated with ring chromosomes?

Answer 12

Ring chromosome 20 which is especially associates with epilepsy in children there are just over 50 cases of this which occur sporadically and have individuals who have mild learning difficulites, behavioural problems and can be difficult to control
There is ring chromosome 13 and 14 which are associated with mental retardation and dysmorphic facial features
Ring chromosome 15 which is associated with mental retardation, dwarfism and microencephaly

Question 13

What is Williams syndrome/

Answer 13

This is the result of a deletion in chromosome 7q with the major identifying characterisitcs being rare neurodevelopmental disorder causing a distinctive elfin face
A low nasal bridge
Unusually cheerful demeanor and at ease with strangers
Developmental delay
Cardiovascular problems
And hypersensitive hearing

Question 14

How can testing for genetic disorders happen?

Answer 14

There can be parental testing where the chromosomal and genetic analysis of a fetus can be determined by analysis of cultured cells from the amniotic fluid there can also be non-invasive testin using fetal DNA in maternal plasma as this represents a mean of 15% of the DNA in maternal plasma

Question 15

Who is commonly tested for genetic disorders?

Answer 15

Preimplantation routinely undergoes genetic screening such as PGS or aneuploidy screening which involves checking the chromosome of embryos conceived by IVF of ICSI
Additionally women over 35 are frequently tested as well as those with a family history of chromosomal problems or those with a history or recurrent miscarriage

Question 16

What are the differences and similarities between Array CGH and SNP arrays?

Answer 16

Both these assays screen 24 chromosomes and detect unbalanced robertsonian translocations
Both of the assays are capable of detection of some unbalanced reciprocal translocations , CGH is also capable of detecting some haploidy and triploidy while SNPs can detect all of these as well as detection of uniparental disomy, determination of the parental origin of trisomies and monosomies, determination of whether the aneuploidy arose during mitosis or meiosis, confirmation of genetic parentage and extraneous DNA contamination all of which are not able to be cone with CGH

Question 17

What is complex or multifactorial inheritance?

Answer 17

This is responsible for a number of developmental disorders which result in a number of congenital malformations
It is the result of the combinational effect of small variations in a number of genes that can produce or predispose to a serious defect
They tend to run in families but have unpredictable patterns of inheritance
Plays a role in 5% of the paediatric population and 60% of the entire population

Question 18

What is an example of a complex disorder?

Answer 18

Spina bifida
This is a congenital problem of neural tube development which may affect up to 1:2500 new borns, these individuals have a fluid filled sac on their back covered in skin along with various other signs and symptoms
It is likely caused by the interaction of multiple genetic and environmental factors such as MTHFR, folate deficiency and exposure to some anti-seizure medications during pregnancy

Question 19

What can be the effect of a loss of function mutant?

Answer 19

The product may have a reduced amount or activity (hypomorph) or no function (amorph)
These tend to recessive although there are two common exceptions known as haploinsufficiency (one copy is insufficient to produce the required amount of the product) or dominant negative where the defective gene interferes with the function of the wild type copy

Question 20

How can gene function be reduced or abolished?

Answer 20

Through an insertion or deletion
Disruption of the gene structure
Nonsense/missense and frameshift mutations
Prevention of the promoter from working
Destabilizing the mRNA
Prevention of correct splicing
Prevention of post transcriptional processing
Prevention of the correct localisation of the product

Question 21

What are splicing mutations?

Answer 21

Mutations which alter important splice site signals leading to intron retention or exon skipping
There can also be mutations of sites that are not normally important in RNA splicing leading to activation of cryptic splice sites

Question 22

What are gain of function mutations?

Answer 22

The mutant product may function in an abnormal way
Tend to be dominant
Common in cancer
Occurs in hereditary pancreatitisis

Question 23

What are the mechanisms of gain of function mutations?

Answer 23

Overexpression
Receptor permanently on
Acquiring a new substrate
Ion channels are inappropriately open
Protein aggregation (occurs in huntingtons disease)
Expression at the incorrect time in development
Expression in the incorrect tissue