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
De novo dominant disease
Sporadic disease caused by new
mutation in sperm/egg
- Recurrence risk in siblings is usually low
- No family history
- Risk increases with parental age
Mosaicism
Presence of more than one genetic subtype of
genetically-related cells
• Germline mosaicism in unaffected parent –
apparent sporadic disease in child, may have a
second affected sibling
• Somatic mosaicism in child – arises postfertilisation
– E.g. mosaic monosomy 7
Mosaicism = presence of >1 genetic subtype of genetically-related cells Germline = cells that produce the gametes (sperm/egg) Somatic = all other cells of the body except the gametes
Mitochondrial inheritance
Maternal inheritance (mitochondria from ovum)
- Severity can be affected if there is a mixed population of mitochondria (heteroplasmy)
- Maternally-inherited diabetes and deafness (MIDD)
- Leber hereditary optic neuropathy (LHON)
Trinucleotide repeat disorders
Unstable expansion of a trinucleotide repeat
• Show anticipation
– due to triplet expansion during meiosis
– increased clinical severity and earlier age of onset in
successive generations
Trinucleotide = three DNA bases (e.g. CTG) Anticipation = increasing severity of disorder in subsequent generations
• Fragile X syndrome (CGG) (1/5,000 males)
– X-linked recessive, most common inherited cause
of learning difficulties, behavioural problems
• Huntington disease (CAG) (1/10,000)
– autosomal dominant, gradual loss of motor
function and coordination, physical, cognitive and
psychiatric features
• Myotonic dystrophy (DM) (CTG) (1/8,000)
– autosomal dominant, most common adult
muscular dystrophy
Epigenetics
Heritable changes caused by modification of gene
expression rather than alteration of the genetic code itself
• DNA methylation
• Histone modifications
• Non-coding RNA
Genomic imprinting
Most genes are expressed from both alleles
• A few (100-150 genes) are expressed only when
inherited from one parent
• Methylation (on/off) status depends on parent-of-origin
Genomic imprinting = gene expression dependent on parent-of-origin
Prader-Willi/Angelman syndromes
2 distinct genetic disorders caused by differential
expression of the same region of chromosome 15 (15q.1)
• Prader-Willi syndrome(PWS) results when the paternal 15q.1
chromosome is deleted since the maternal PWS region is inactive
(imprinted)
Ømental retardation, severe eating disorder, uncontrollable
appetite, obesity, diabetes
• Angelmans syndrome (AS), results when the maternal 15q.1
chromosome is deleted since the paternal AS gene (UBE3A) is
inactive (imprinted)
Øbehavioural problems, mental retardation, hand flapping,
absent speech, ataxia
• Mutation results in no gene expression at imprinted region
Multifactorial inheritance
Interaction between genetic and environmental factors • Cluster in families but incidence in close family members is <5% Due to genetic variation • Polygenic inheritance involving many different genes each with small additive effects • Risk loci identified in Genome-Wide Association Studies (GWAS) • Many common diseases, including: Asthma Cancer Hypertension Type 1 diabetes Obesity Multiple sclerosis Rheumatoid arthritis Schizophrenia Type 2 diabetes
Summary
Single gene disorders can be autosomal dominant
(AD), recessive (AR), or X-linked (XL)
– AD diseases can show reduced penetrance or be
due to new mutations
– Trinucleotide repeat disorders can show anticipation
– Sex-specific inheritance (or parent-of-origin) effect
could be X-linked, mitochondrial or imprinted
– Understanding the mode of inheritance is important
for calculating familial risk
• Common diseases generally have polygenic/
complex inheritance
