Lecture 6 :Genetic diseases –categories, inheritance patterns & impact Flashcards
Name a purely genetic disease?
Duchenne muscular dystrophy
What are characteristics of genetic diseases?
Rare
Genetics simple
Unifactorial
High recurrence rate
What are characteristics of environmental diseases?
Common
Genetics complex
Multifactorial
Low recurrence rate
What are the three points on the genes vs environment triangle?
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.
Where would Achondroplasia land in the triangle?
Achondroplasia – single gene with predominant effect on stature
Where would a stroke land in the triangle?
Stroke – multifactorial with environment and polygenic factors – for some there may be single gene influence (Cadasil)
What does the acronym CADACIL stand for?
cerebral
autosomal
dominant
arteriopathy with
subcortical
infarcts and
leukoencephalopathy (Cadasil
Define single gene:
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
Define Somatic mutations:
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
Define Chromosomal mutations:
an imbalance or rearrangement in chromosome number or structure e.g. aneuploidy, deletion, translocation
Define multifactorial/ Complex mutations:
multiple genes (genetic predisposition) interact with environmental factors to determine risk e.g. type 2 diabetes, ischaemic heart disease.
What are the single gene modes of inheritance?
Autosomal Dominant
Autosomal Recessive
X-linked
Mitochondrial
Properties of DNA:
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
What key is used when discussing inheritance patterns?
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
Define autosomal dominance inheritance?
A single mutated gene (heterozygous state) is sufficient to cause the disease
Autosomal dominance what is the ratio between male and female?
Males and females equally affected
What is the chance of autosomal dominance inheritance of disease?
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%
What are some example of autosomal dominant inheritance diseases?
Marfan Syndrome
Huntington disease
Myotonic dystrophy
Chromosome deletions and duplications
Chromosome deletion e.g. 22q11 deletion - (DiGeorge) syndrome
What is Penetrance?
The frequency with which a specific genotype results in a phenotype, usually given as a percentage.
Can penetrance alter with age?
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
What is incomplete penetrance?
not all family members who inherit the mutation develop the disorder – e.g. BRCA1 mutations confer a 80% lifetime risk of developing breast cancer
What is expressivity?
Variation in phenotypic severity - the extent to which a heritable trait is manifested by an individual.
What are some examples of expressivity?
Marfan Syndrome: aortic dilatation, lens dislocation, stretch marks
BRCA1 mutation: +/- ovarian cancer, breast cancer
What is anticipation?
- 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.
What are some examples of anticipation?
Huntington’s disease
Myotonic dystrophy
special type of mutation
What are some examples of anticipation?
Huntington’s disease
Myotonic dystrophy
special type of mutation
What is a de novo mutation?
- 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
What are the chances of inheriting an autosomal recessive Inheritance?
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
Does Autosomal recessive diseases affect male and females the same?
Affects males and females equally
What are some characteristics of autosomal recessive diseases?
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
What is consanguinity?
the fact of being descended from the same ancestor
What are some examples of an autosomal recessive disease?
Sickle cell disease (HBB)
Cystic fibrosis (CFTR)
Many of the metabolic disorders
(Often enzyme loss
e.g. PKU (phenylalanine hydroxylase, PAH))
Haemochromatosis (HFE)
Are recessive or dominant mutations more common?
Recessive mutations are much commoner than dominant
Carriers are healthy
We all carry lots of recessive mutations
Occasional heterozygote advantage
What is X- linked inheritance?
The mutation is located on the X chromosome
Can you have male to male transmission of X- linked inheritance?
Cannot have male to male transmission
What happens of the disease is X - linked recessive?
Only males affected
Females unaffected carriers
What happens of the disease is X - linked dominant?
Mildly through to fully affected
Males often more severe than females – disease-specific
What are some examples of X linked inheritance?
Duchenne muscular dystrophy
Fragile X syndrome
Red / green colour-blindness
Haemophilia
What are the chances of obtaining an X - linked inheritance recessive disease with affected mother?
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
What are the chances of obtaining an X - linked inheritance recessive disease with affected father?
All daughters are carriers
All sons are unaffected (no male to male transmission)
What can females have such a variable phenotype with X- linked inheritance?
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
What are two main factors that influence phenotype with X linked inheritance?
Two main factors influence phenotype
X inactivation
XL dominant vs. XL recessive
Characteristic of individual gene / disorder
What is X - inactivation (Lyonisation)?
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.
what are some characteristics of X - inactivation?
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
In a carrier female, what percentage of cells do we expect to express the normal gene? ( X - inactivation)
In a carrier female, we expect ~50% of cells to express the normal gene
What is skewed X - inactivation?
if by chance most cells inactivate the normal X chromosome = significant phenotype
What is tissue variability in X - inactivation, female carriers?
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)
Which is rarer: XL dominant or XL recessive?
XL dominant
Which disease have a Phenotype only in females, lethal in males ? (X linked dominant)
Rett syndrome
Orofaciodigital syndrome (OFD1)
Which diseases have
Phenotype only in females, silent in males? (X linked dominant)
Craniofrontonasal syndrome
What is mitochondrial Inheritance?
The human mitochondrion has its own small set of genes
(16-kb circular genome
27 genes)
Where is our mitochondria inherited from?
The sperm head has no mitochondria
All our mitochondria are inherited from our mother
Does mitochondrial Inheritance affect females or males?
Rare, males and females affected equally
An affected mother will give all her children the mutation
Why does mitochondrial inheritance have a highly variable expressivity?
Each cell has many mitochondria
Each mitochondrion has multiple genome copies
Cytoplasmic inheritance
Proportions of mutant genome can vary widely
Heteroplasmy
Will children of an affected man be affected in mitochondrial inheritance?
No children of an affected man will be affected
What is mosaicism?
If a new mutation occurs not during gametogenesis but post-zygotically (somatically), the progeny of the mutant cell will also be mutant
What are some characteristics of mosaicism?
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
Why is family history taking important?
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
key questions to ask while drawing a family pedigree?
“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
Complications of consanguinity?
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
