Clinical Genetics (2) Flashcards
Classification of genetic disorders
- Multifactorial/complex
- Single gene
- Chromosomal
- Mitochondrial
- Somatic mutations
Single gene modes of inheritance
Autosomal dominant, Autosomal recessive, X-linked, Mitochondrial
Autosomal Dominant Inheritance
- Males and females equally affected
- Offspring 1 in 2 change inheriting mutation
Examples of AD inheritance
- Myotonic dystrophy
- Marfan syndrome
- Huntington disease
- 22q11 deletion syndrome
Penetrance
The frequency with which a specific genotype is expressed by those individuals that possess it, usually given as a percentage
By what age is Huntington disease 100% penetrance?
80
Incomplete penetrance
Not all relatives who inherited the mutation develop the disorder e.g. BRAC1 80%
Expressivity
Variation in expression, the extent to which a heritable trait is manifested by an individual
Anticipation
Symptoms of a genetic disorder become apparent at an earlier age as it passes from one generation to the next and normally increases in severity
Examples of anticipation illnesses
Myotonic dystrophy and Huntington’s disease
New dominant/de novo mutation
New mutation that has occurred during gametogenesis/early embryonic development
Examples of AR inheritance
- Cystic fibrosis
- Many metabolic disorders
- Haemachromatosis
- Sickle cell disease
Do males are females suffer more from X-linked?
Males, females are variably affected
Cannot have male to …. transmission
male
What influences XL expression in females?
X inactivation and XL dominant (rare) vs XL recessive
Can you predict female phenotype on prenatal testing?
No
What is lyonisation?
Random inactivation of one of the X chromosomes (X-inactivation)
When does X-inactivation occur?
Early embryogenesis and once activated remains inactive throughout and descendants
Are all the genes switched off in an inactivated X?
Most but not all
Barr body
Condensed X
Skewed X-inactivation
Random preference for ‘normal’ X chromosome to be inactivated
Tissue variability
Random preference for X with mutation to be active in crucial tissue group
Example of tissue variability
Muscles in Duchenne muscular dystrophy
XL dominant examples
- Rett syndrome (lethal in males)
- Fragile X syndrome
XL recessive examples
- Red-green colour blindness
- Haemophilia
- Duchenne muscular dystrophy
- Carrier girls affected if X-inactivation switches normal X off
Examples of mitochondrial inheritance
Maternally inherited diabetes and deafness
Is mitochondrial inheritance from your father or mother?
Mother, as sperm head has no mitochondria (give all her children the mutation)
How many genes in mitochondrial DNA?
27
Is mitochondrial inheritance rare or common?
Rare
Expressivity of mitochondrial inheritance
is variable
Consanguinity
Couples who are ‘blood’ relatives (5-6% risk of congenital birth defect)
