Lecture 16: Medical Genetics

Question 1

What are the 4 categories of Genetically detemined diseases

Answer 1

Single gene, chromosomal, multifactorial and somatic cell disorders

Question 2

What type of disorder is B thalassaemia and what condition is it

Answer 2

Inherited single gene disorder due to autosomal recessive mutation of the HBB gene. Causes reduced synthesis of haemoglobin beta chains

Question 3

What causes Downs syndrome- chromosomal disorder

Answer 3

Due to non disjunction during metaphase, and translocation. Band Q22 genes important. Extra copy of chromosome 21= extra proteins being made

Question 4

What causes multifactorial disorders

eg. diabetes, hypertension, coronary artery disease, schizophrenia, cleft lip, cleft palate, most congenital heart disease

Answer 4

Interaction of multiple genes with minor effects each and then interaction with the environment to manifest the disease.

For common gene combinations relating to a specific disease they can create polygenic risk scores

Question 5

What are the transmittability of somatic cell genetic disorders

Answer 5

Can be inherited by the daughter cells of somatic cells but not able to passed onto progeny as mutation is not in germ cells.

Question 6

For somatic cell genetic disorder Cancer, what are different ways it can arise/how many genes can it affect

Answer 6

Arise from loss of whole chromosome leading to loss of tumour suppressing genes or can arise from single gene mutation in genes that control cell growth and.

Question 7

Define mutation

Answer 7

Any permanent heritable change in the sequence of genomic DNA from its natural state

Question 8

Define polymorphism

Answer 8

The presence of natural variation in the DNA sequence of a gene that leads to two or more alternate genotypes being maintained in the population as they don’t have obv adverse effects

Question 9

Compare Silent, Missense, Nonsense, mutation

Answer 9

Silent: single base change which doesn’t result in amino acid change

Missense: single base change which does result in amino acid change-> phenotype may be ok

Nonsense: single base change that changes amino acid to stop codon

Question 10

What is a frameshift and a Splice donor/ acceptor

Answer 10

Frameshift (aka indel): insertion or deletion of bases in anything other than multiple of 3

Splice donor/ acceptor: Alteration of sequences for accurate splicing of introns

Question 11

What do you look for to help decide if a mutation is pathogenic

Answer 11

• You can put the mutation back into cells in the lab (structure function studies/in vitromutagenesis)
• See if this specific amino acid has been conserved over evolution
• Looking for prematurely stopped protein (truncated) as most likely pathogenic
• Look to see if RNA splicing affected
• If inheritable see if the mutation segregate with disease in the family

Question 12

What are the phenotypic consequences of mutations

Answer 12

-Gain in function; increased amount of activity of product
-Loss of function:
Reduced amount or reduced activity of product with usually minimal effect unless both alleles are affected

Question 13

How does the way alleles interact affect the phenotypic outcome of loss of function mutations

Answer 13

• Null alleles can result in no product or function leading to Haploinsufficiency - 50% product level results in altered phenotype
• Some heterozygotes loss of function mutation is Dominant Negative where abnormal product interferes with product of normal allele

Question 14

Define consanguinity, dizygotic vs monozygotic twins, obligate carrier and proband in the construction of a pedigree

Answer 14

Consanguinity: inbreeding or individuals 2nd cousins or closer

dizygotic= non identical monozygotic= identical twins,

obligate carrier= carrier of gene but unaffected

proband= person serving as starting point for genetic study of family

Question 15

What does coloured in shape on pedigree mean

Answer 15

Affected phenotype

Question 16

What is lyonisation

Answer 16

The random inactivation of parts of one X chromosome in female somatic cells as they have an X from mum and an X from dad

Question 17

Compare X linked recessive and X linked dominant inheritance

Answer 17

X linked recessive: affects more males vs XLD affects more females but more mildly due to lyonisation

XLR & XLD: no male to male transmission
but all daughters of affected males carry the gene

XLR: less chance of females being affected
XLD: same 50% chance of offspring being affected

Question 18

How do you tell apart X linked dominant inheritance and Y linked inheritance from autosomal dominant

Answer 18

There will be no transmission from male to male for XLD

For Y linked there is only transmission from males unless its a new mutation

Question 19

What is difference between variable penetrance and variable expression

Answer 19

Variable penetrance: Qualitative difference between phenotype expression of the the same mutation (failure of dominant condition to manifest)

Variable expression: quantitative difference of phenotypic expression- the way its expressed

Question 20

What is New mutations vs Germline mosaicism

Answer 20

New: A mutation that occurs very early in embryogenesis leading to the daughter populations of those cells carrying the mutation while others not so not actually passed from parent.
For Germline mosaicism it just means this new mutation affects a proportion of the gametes and not in somatic cells

Question 21

Compare allelic heterogeneity and locus heterogeneity

-> the relationship between where the mutation is to resulting in the disease

Answer 21

Allelic : lots of different mutations at the same gene which cause the same disease

Locus: same disease can be caused by mutations in different genes at different loci, with some different modes of inheritance