Lecture 2 - Genetic Diseases Flashcards
Genetic diseases
• Any disease involving your genes, so includes:
– single gene disorders (monogenic)
– multifactorial disorders (polygenic + non-genetic)
– chromosomal disorders
What is the clinical relevance?
- Thousands of diseases have a genetic component
- 50% of major congenital abnormalities (2-3% of newborns) have a genetic component
• 50% of all childhood blindness, deafness and severe
learning difficulties have a genetic origin
• One in 17 people are born with or develop a rare disease during their lifetime. Around 80% of rare diseases is thought to have an underlying genetic cause, with 50% of new cases of rare diseases being identified in children.
Congenital/inherited = a condition present at birth Acquired/Somatic = not inherited, not present at birth
The human genome
The haploid genome contains 3 billion base pairs
of DNA packaged into 23 chromosomes
Most cells are diploid, with one copy of each chromosome inherited from each parent
=> 22 pairs of autosomes
=> 1 pair of sex chromosomes
Haploid = containing one copy of each chromosome Diploid = containing two copies of each chromosome Genome = the entire genetic information of an individual
Genotypes
Locus (plural: loci) = position on chromosome
Allele = alternative forms of gene/locus/variant
Homozygous = two copies of same allele at same locus (genotype AA or BB)
Heterozygous = different alleles at same locus (genotype AB or BA)
Mutation vs variant vs polymorphism
Mutation often used to mean disease-causing allele
(more properly should be used only when mutational
process occurs in DNA)
Polymorphism usually means alleles that are present in
>1% of the population
Variant encompasses all loci where there are multiple
alleles in the human population, regardless of
commonness or pathogenicity
Simple modes of inheritance
Single gene characteristics and traits are inherited in a
predictable way (Mendelian or monogenic)
– Autosomal dominant
– Autosomal recessive
– X-linked
Autosomal = carried on an autosome (chromosomes 1-22)
X-linked = carried on the X chromosome
Dominant = trait is present when only one mutant allele is present
Recessive = trait is present when both alleles of gene are mutated
Autosomal dominant inheritance
• 50% risk in offspring • Males and females equally affected • Affected individuals should have an affected parent • Tends to occur in every generation
e.g. Familial hypercholesterolaemia (FH)
• Affects 1 in 500 in most populations
• Raised cholesterol (>7.5 mmol/l)
• Family history of premature coronary heart disease
• Mutation of LDL receptor (LDLR) or APOB
e.g. Huntington disease (HD)
Incidence 1/10,000
• Onset typically 35-55 year of age
• Movement, cognitive and psychiatric
Mechanism in HD = ‘gain of function’
Autosomal dominant diseases can show:
Reduced penetrance
– heterozygous but no clinical phenotype
– disease skips a generation
• Variable expressivity
– individuals show only some of the symptoms
• Late onset
– disease not apparent until already passed on
Penetrance = proportion of individuals with a particular genotype who show
features of the condition
Expressivity = phenotypic variability and severity with which a given genotype
shows in individuals penetrant for the condition.
Autosomal recessive inheritance
- 25% risk in offspring from two carriers
• Males and females equally affected
• Often no previous family history (unless consanguineous)
• Mutation may be homozygous or compound heterozygous
e.g. Cystic fibrosis (CF)
• Commonest autosomal recessive disease affecting Caucasians
• Incidence 1/2,500 – 250 babies/year
• Carrier frequency is ~1/25
• Mutations in CF transmembrane conductance regulator (CFTR)
• Main defects in the lungs and pancreas caused by thickened mucus
e.g. Phenylketonuria (PKU) Incidence 1/10,000 • Severe learning difficulties • Epilepsy • Treated by restricting phenylalanine intake
Mechanism in PKU = ‘loss of function’
X-linked (recessive) inheritance
No male-to-male transmission
• Predominantly affects males
• Carrier females less severely affected
Hemizygous = having a single copy of a gene, e.g. male X chromosome
X-linked (dominant) inheritance
Usually only females affected (usually lethal in males)
• Excess of (male) miscarriages
• Female-female transmission
X-inactivation
X-inactivation can affect severity of X-linked diseases in girls.
X-inactivation = one of the copies of the X chromosome present in female is inactivated; may be different in different cells
Examples of X-linked Inheritance
Recessive (mainly affects males)
Haemophilia A and B – blood clotting disorders
Duchenne muscular dystrophy – chronic muscle wasting
Dominant (mainly affects females)
Rett syndrome – delayed development from around 1 year, autistic features, absent speech, lose ability to walk. Mostly affects females, generally embryonic lethal in males.
The importance of pedigrees
Patterns of inheritance can be more easily
visualised in a pedigree
• Related symptoms among family members may
refine the diagnosis
• Calculate risk in other family members and future
pregnancies
• Helps to inform testing, surveillance, management
and treatment in other family members
• Provides a record which can be updated with new
information
Complex modes of inheritance
Some diseases do not follow normal predictable
patterns of inheritance (non-Mendelian)
– De novo mutations – Mosaicism – Mitochondrial inheritance – Trinucleotide repeat disorders – Disorders of genomic imprinting
• The majority of traits are caused by many genes
(polygenic) and inheritance is therefore
complex
