Lecture 6 :Genetic diseases –categories, inheritance patterns & impact

Question 1

Name a purely genetic disease?

Answer 1

Duchenne muscular dystrophy

Question 2

What are characteristics of genetic diseases?

Answer 2

Rare
Genetics simple
Unifactorial
High recurrence rate

Question 3

What are characteristics of environmental diseases?

Answer 3

Common
Genetics complex
Multifactorial
Low recurrence rate

Question 4

What are the three points on the genes vs environment triangle?

Answer 4

100% environmental
Polygenic
Single gene
For a given disorder, the balance of genetic and environmental factors can be represented by a point somewhere within this triangle.

Question 5

Where would Achondroplasia land in the triangle?

Answer 5

Achondroplasia – single gene with predominant effect on stature

Question 6

Where would a stroke land in the triangle?

Answer 6

Stroke – multifactorial with environment and polygenic factors – for some there may be single gene influence (Cadasil)

Question 7

What does the acronym CADACIL stand for?

Answer 7

cerebral
autosomal
dominant
arteriopathy with
subcortical
infarcts and
leukoencephalopathy (Cadasil

Question 8

Define single gene:

Answer 8

a mutation in a single gene = Mendelian inheritance – AD, AR, XL e.g. achondroplasia, cystic fibrosis, Duchenne muscular dystrophy
7000 known

Mitochondrial: a mutation in mitochondrial DNA

Question 9

Define Somatic mutations:

Answer 9

postzygotic mutation(s) occurring in a somatic cell, giving rise to a defined population of mutant cells that result in disease e.g. genetic mosaicism, breast cancer

Question 10

Define Chromosomal mutations:

Answer 10

an imbalance or rearrangement in chromosome number or structure e.g. aneuploidy, deletion, translocation

Question 11

Define multifactorial/ Complex mutations:

Answer 11

multiple genes (genetic predisposition) interact with environmental factors to determine risk e.g. type 2 diabetes, ischaemic heart disease.

Question 12

What are the single gene modes of inheritance?

Answer 12

Autosomal Dominant
Autosomal Recessive
X-linked
Mitochondrial

Question 13

Properties of DNA:

Answer 13

46 chromosomes (in diploid cells)
23 pairs
1000s of genes on each chromosome
2 copies of every gene (apart from X & Y)
Gametes contain 23 chromosomes with 1 copy of each gene

Question 14

What key is used when discussing inheritance patterns?

Answer 14

A = “healthy”, “normal” gene/chromosome
a = gene/chromosome with disease mutation
We all have 2 copies of each gene (except X and Y genes in males)
AA = person with 2 “normal” genes
Aa = person with 1 “normal” gene copy + 1 gene copy with the disease mutation

Question 15

Define autosomal dominance inheritance?

Answer 15

A single mutated gene (heterozygous state) is sufficient to cause the disease

Question 16

Autosomal dominance what is the ratio between male and female?

Answer 16

Males and females equally affected

Question 17

What is the chance of autosomal dominance inheritance of disease?

Answer 17

Offspring of affected person has a 50% (1 in 2) chance of inheriting the disease-causing mutation
The disease gets passed from one generation to the next

Affected individuals are heterozygous for the mutation (one copy of mutation / one normal gene)
Chance that offspring affected 2/4 = 1/2 = 50%
Chance that offspring unaffected 2/4 = 1/2 = 50%

Question 18

What are some example of autosomal dominant inheritance diseases?

Answer 18

Marfan Syndrome
Huntington disease
Myotonic dystrophy
Chromosome deletions and duplications
Chromosome deletion e.g. 22q11 deletion - (DiGeorge) syndrome

Question 19

What is Penetrance?

Answer 19

The frequency with which a specific genotype results in a phenotype, usually given as a percentage.

Question 20

Can penetrance alter with age?

Answer 20

Yes - May alter with age, e.g. a Huntington’s disease mutation may be 100% penetrant at 80 years, but at 50 years only 50% penetrant

Question 21

What is incomplete penetrance?

Answer 21

not all family members who inherit the mutation develop the disorder – e.g. BRCA1 mutations confer a 80% lifetime risk of developing breast cancer

Question 22

What is expressivity?

Answer 22

Variation in phenotypic severity - the extent to which a heritable trait is manifested by an individual.

Question 23

What are some examples of expressivity?

Answer 23

Marfan Syndrome: aortic dilatation, lens dislocation, stretch marks
BRCA1 mutation: +/- ovarian cancer, breast cancer

Question 24

What is anticipation?

Answer 24

• the symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next. There may also be an increase in the severity of symptoms.

Question 25

What are some examples of anticipation?

Answer 25

Huntington’s disease Myotonic dystrophy special type of mutation

Question 26

What are some examples of anticipation?

Answer 26

Huntington’s disease Myotonic dystrophy special type of mutation

Question 27

What is a de novo mutation?

Answer 27

- a new mutation that has occurred during gametogenesis The parents are not affected and do not have the mutation in their somatic tissues. The child is the first to be affected in the family, but can pass the mutation to his/her own children

Question 28

What are the chances of inheriting an autosomal recessive Inheritance?

Answer 28

Affected individuals are homozygous or compound heterozygous for the mutation (two mutant copies) Aa = carrier = unaffected Risk of offspring being affected = 1/4 = 25% Risk of unaffected offspring being a carrier = 2/3

Question 29

Does Autosomal recessive diseases affect male and females the same?

Answer 29

Affects males and females equally

Question 30

What are some characteristics of autosomal recessive diseases?

Answer 30

Disease usually seen in one generation Does not tend to pass from one generation to next – parents usually unaffected Offspring of affected individual has low risk of disease Exceptions to this include parental consanguinity Relatives may often be asymptomatic carriers of the disease Testing for this not necessarily relevant

Question 31

What is consanguinity?

Answer 31

the fact of being descended from the same ancestor

Question 32

What are some examples of an autosomal recessive disease?

Answer 32

Sickle cell disease (HBB) Cystic fibrosis (CFTR) Many of the metabolic disorders (Often enzyme loss e.g. PKU (phenylalanine hydroxylase, PAH)) Haemochromatosis (HFE)

Question 33

Are recessive or dominant mutations more common?

Answer 33

Recessive mutations are much commoner than dominant Carriers are healthy We all carry lots of recessive mutations Occasional heterozygote advantage

Question 34

What is X- linked inheritance?

Answer 34

The mutation is located on the X chromosome

Question 35

Can you have male to male transmission of X- linked inheritance?

Answer 35

Cannot have male to male transmission

Question 36

What happens of the disease is X - linked recessive?

Answer 36

Only males affected Females unaffected carriers

Question 37

What happens of the disease is X - linked dominant?

Answer 37

Mildly through to fully affected Males often more severe than females – disease-specific

Question 38

What are some examples of X linked inheritance?

Answer 38

Duchenne muscular dystrophy Fragile X syndrome Red / green colour-blindness Haemophilia

Question 39

What are the chances of obtaining an X - linked inheritance recessive disease with affected mother?

Answer 39

1/4 (25%) normal girl + 1/4 (25%) carrier girl 1/4 (25%) normal boy + 1/4 (25%) affected boy Half of sons affected Half of daughters carriers

Question 40

What are the chances of obtaining an X - linked inheritance recessive disease with affected father?

Answer 40

All daughters are carriers All sons are unaffected (no male to male transmission)

Question 41

What can females have such a variable phenotype with X- linked inheritance?

Answer 41

Most XL carrier females are asymptomatic or have mild symptoms However, they can sometimes have significant symptoms Sometimes cannot predict a female phenotype accurately on prenatal testing

Question 42

What are two main factors that influence phenotype with X linked inheritance?

Answer 42

Two main factors influence phenotype X inactivation XL dominant vs. XL recessive Characteristic of individual gene / disorder

Question 43

What is X - inactivation (Lyonisation)?

Answer 43

The process of random inactivation of one of the X chromosomes in cells with >1 X chromosome Compensates for the presence of the double X gene dosage.

Question 44

what are some characteristics of X - inactivation?

Answer 44

Occurs whenever there are 2 (or more) X chromosomes in a cell Early in embryogenesis Random choice of which X is silenced Once inactivated, an X chromosome remains inactive throughout the lifetime of the cell and all its descendants Most (but not all) genes switched off on the inactivated X

Question 45

In a carrier female, what percentage of cells do we expect to express the normal gene? ( X - inactivation)

Answer 45

In a carrier female, we expect ~50% of cells to express the normal gene

Question 46

What is skewed X - inactivation?

Answer 46

if by chance most cells inactivate the normal X chromosome = significant phenotype

Question 47

What is tissue variability in X - inactivation, female carriers?

Answer 47

Tissue variability: if by chance most cells in a crucial tissue inactivate the normal X = significant phenotype e.g. - muscle (Duchenne Muscular dystrophy) - liver sinusoidal & vascular endothelial cells (haemophilia)

Question 48

Which is rarer: XL dominant or XL recessive?

Answer 48

XL dominant

Question 49

Which disease have a Phenotype only in females, lethal in males ? (X linked dominant)

Answer 49

Rett syndrome Orofaciodigital syndrome (OFD1)

Question 50

Which diseases have Phenotype only in females, silent in males? (X linked dominant)

Answer 50

Craniofrontonasal syndrome

Question 51

What is mitochondrial Inheritance?

Answer 51

The human mitochondrion has its own small set of genes (16-kb circular genome 27 genes)

Question 52

Where is our mitochondria inherited from?

Answer 52

The sperm head has no mitochondria All our mitochondria are inherited from our mother

Question 53

Does mitochondrial Inheritance affect females or males?

Answer 53

Rare, males and females affected equally An affected mother will give all her children the mutation

Question 54

Why does mitochondrial inheritance have a highly variable expressivity?

Answer 54

Each cell has many mitochondria Each mitochondrion has multiple genome copies Cytoplasmic inheritance Proportions of mutant genome can vary widely Heteroplasmy

Question 55

Will children of an affected man be affected in mitochondrial inheritance?

Answer 55

No children of an affected man will be affected

Question 56

What is mosaicism?

Answer 56

If a new mutation occurs not during gametogenesis but post-zygotically (somatically), the progeny of the mutant cell will also be mutant

Question 57

What are some characteristics of mosaicism?

Answer 57

Distribution of mutant cells unpredictable May include the gonads, giving rise to a risk of transmission May result in attenuated forms of Mendelian disorders May involve mutations that are lethal if non-mosaic

Question 58

Why is family history taking important?

Answer 58

Helps make a diagnosis Helps clarify risk for our patient Helps us understand our patient’s point of view Helps us identify who else may be at risk Helps us understand the patient’s support network

Question 59

key questions to ask while drawing a family pedigree?

Answer 59

“Do the children all have the same dad (mum)?” -- Half-siblings “Do either of you have any other children from other relationships?” -- Step-brothers/sisters

Question 60

Complications of consanguinity?

Answer 60

Couples who are “blood” relatives Potentially share recessive gene mutations Risk of congenital birth defect 5-6% (2-3% gen pop), if no family history of genetic condition