Lecture 14- Medical Genetics

Question 1

Single Gene Disorders

Answer 1

one gene changes. Leads to disease of phenotype
Result from mutation in one (dominant) or both (recessive) of a pair of genes.
-Autosomal, X chromosomal, Y Chromosomal
Eg) B-thalassemia
-can manifest in a variety of organ system, HUGE broad reaching effect.

Question 2

Chromosomal Disorders

Answer 2

Multiple genes change, leading to major change in cell. Usually not compatible with life as effect is usually to big. Small number of disorders are
Eg) Down syndrome - trisomy 21 (3 copies of chromosome 21, error in cell division)

Question 3

Multifactoral Genetic disorders

Answer 3

multiple genes interact with the environment and pathogens.
Can be MAJOR or MINOR effect.
-not well understood.

diabetes, schizophrenia

Question 4

Somatic cell disorders

Answer 4

Not in testes or ovaries.
Not transmitted to subsequent generations
eg) cancer
-Single gene: APC gene

-Whole chromosome: chromosome 11 (example) was lost in the tumor it will still show on scans due to normal cells within the tumor having the chromosome. This is enough to keep the tumor alive.

Question 5

Causes of Down syndrome.

Why does it increase with age?

Answer 5

Trisomy 21 (3 copies of chromosome 21)
Risk increases with maternal age -due to non-disjunction, metaphase 1
-OR Translocation (cutting and rejoining, you could get 2 long arms) 

Down syndrome was discovered DECADES before it was understood.

Question 6

Mutation

Answer 6

Permanent heritable change in the sequence of genomic DNA

-alteration from natural state, can be benign or disease-causing

Question 7

Polymorphism

Answer 7

The occurrence of 2+ alternative genotypes, promotes diversity, don’t really give any advantages,just make us different.
-Natural variations within genome, usually no adverse effects

SNPs or Single Nucleotide Polymorphisms (1 per 100-1000) difference in gene. Good markers, link to a change in genes.

Question 8

Types of Mutations

Answer 8

Silent: single base change > no amino acid change

Missense: single base change > amino acid change

Nonsense: Single base change > changes amino acid to stop codon

Frameshift: insertion/deletion any thing but multiple of three
‘Indel’ is inser/dele of more then one

Splice donor/acceptor: alteration of sequences, for accurate splicing of introns

Question 9

Sickle Cell Anaemia

Answer 9

Missense mutation
Wildtype: CTC (GAG) for glutamic acid
Missense mutation: CAC (GUG) for valine … the A substitutes the T

Question 10

How do you know if your DNA change is pathogenic?

Answer 10

If missense, ask yourself, “is it at a functionally important site?”
Is the predicted proteins smaller?

Is RNA splicing affected?

Does change correlate with a familt diseas

Question 11

Somatic vs germline mutation

Answer 11

Somatic: in somatic cells, consequences limited to the person

Germline: mutation in cells that forma gametes, changes may be inherited

Question 12

Gain of function mutation

Answer 12

Proteins encoded with mutation produce increased amount or increased product activity
NOT ALWAYS GOOD
eg) malenoma

Question 13

Loss-of-function mutations (null alleles, haploinsufficiency)

Answer 13

Reduced amount or a reduced activity of gene product

If no function at all&raquo_space; NULL ALLELE
Even if there is a null allele, the remaining normal alleles is usually enough, disease prevented, usually minimal phenotypic effect.

Haploinsufficiency: when normal alleles (50% normal) not enough, altered phenotype occurs

Dominant Negative effect

Question 14

Dominant Negative effect

Answer 14

Happens in loss-of-function mutations.

Abnormal mutated allele product interferes with the production of the normal allele

Question 15

How are Single gene disorders understood?

Answer 15

Based on mendels laws

-constructed from pedigree

Question 16

Autosomal patterns of inheritance

Answer 16

Occurs in chromosomes 1-22, in both/either maternal/paternal alleles
Autosomal Dominant:
Autosomal Recessive:

Question 17

Autosomal Dominant

Answer 17

heterozygous, one normal & one abnormal.
50:50 chance of passing on the gene.
Iherited from either sex
So affected person has at least one affected parent
eg) huntingtons

Question 18

Autosomal Recessive

Answer 18

if the gene exists in herterozygous> carrier

If the gene exists homozygous > have disorder

• person usually born to unaffected (carrier) parents
• both sexes affected
• risk increases with parental incest
• 25% chance of affect child (rr) with two carrier parents (Rr)

Question 19

Sex linked inheritance

Answer 19

female : two X chromosomes
Male : one X (mum), one Y (dad)
X-linked dominant inheritance
X-linked reccesive inheritance
Y-linked inheritance

Question 20

X-linked Recessive

Answer 20

• Mainly males affected, as their only X chromosome is affected.
• Affected males usually born to unaffected parents (carrier mum and normal dad)
• no male > male transmission
• all daughers of affected males ar obligate carriers

eg) Haemophilia

Question 21

X-linked Domanant Inheritance

Answer 21

Both sexes affected, but more females.

• child of female has 50% chance of being affected
• child of male if male 0% if female 100% affected

Question 22

Y-linked inheritance

Answer 22

• affects only males
• affected male always have an affected father
• all sons affected

Question 23

What is lyonisation

Answer 23

Random inactivation of parts of one X chromosome in female somatic cells

Question 24

Complication of basic mendelian pedigree patterns

Answer 24

common reccesive condition can look dominate

Variable Penetrance: dominant mutation takes time to get disease

Variable expression

New mutations: brand new non-inherited mutations ‘de novo’
or germline mosaicism

Question 25

Allelic heterogeneity

Answer 25

different mutations at the same locus/gene

eg) cystic fibrosis >100o mutation on CFTR gene

Question 26

Locus heterogeneity

Answer 26

Mutations at different loci