Topic 2 - Forms of Inherited disease Flashcards
What is a genetic disease?
any kind of disease that involves genes
Monogenic
inherited and caused by 1 gene
Multifactorial disease
polygenic and non-genetic (environmental)
Chromosomal disorders
genomes and chromosomes
Not all genetic diseases are
inherited
congenital/inherited =
condition present at birth
acquired/somatic =
not inherited, not present at birth
Human Genome:
- 46 chromosomes (23 pairs) - 22 autosomes - 1 sex chromosome - 20,000 genes across the bases - haploid genome - 3 billion bp of DNA packaged into chromosomes
Haploid
containing 1 copy of each chromosomes
Diploid
containing 2 copies of each chromosomes
Genome
entire genetic information of an individual
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 –
disease causing allele
polymorphism
alleles present in >1% of population
variant
encompasses al loci where there are multiple alleles in human population regardless of commonness or pathogenicity.
Simple modes of inheritance
Single gene characteristics and traits are inherited in a predictable way (Mendelian/monogenic) - Autosomal dominant - Autosomal recessive - X-linked
Monogenic
single gene controlling specific disease
autosomal -
carried on an autosome (ch 1-22)
X linked
carried on X chromosome
Dominant
trait present when only 1 mutant allele is present
Recessive
trait present when both alleles of gene are mutated
Autosomal Dominant inheritance
- Passed down through autosomes - 50% off risk in offspring, most commonly - males and females equally affected - Affected individuals should have an affected parent - Tends to occur in every generation
Example of Autosomal dominant inheritance
Familial hypercholesterolaemia (FH) Hungtington Disease (HD)
Familial hypercholesterolaemia (FH)
- Affects 1/500 people - Number of different mutations in the LDL receptor gene (LDLR) or APOB - Mutations in the gene mean you can’t metabolise cholesterol properly - So raised cholesterol symptom (>7.5mmol/l) - Treated with statin - Family history of premature coronary heart disease - Diagnosing through cascading (testing other family members)
Symptoms of FH
cholesterol deposition tendon xanthomata corneal arcus
Hungtington Disease (HD)
- Incidence = 1/10,000 - if you have the mutation in the HD gene it’s late onset so you definitely will have it - No treatment - Passed down in a dominant way - Onset 35-55 years of age - Movement, cognitive and psychiatric - 50% chance of incidence
Mechanism in HD
gain of function = As a result of a mutation in particular gene, you get expansion of repeats = CAG repeats in Huntington gene is unstable during meiosis and can be expanded due to copy errors. As it gets bigger, the (toxic) protein increases with more and more repeats of a particular amino acid which leads to protein aggregation (clumps of protein in brain). These cause Huntington symptoms over time.
Autosomal Dominant disease 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 2 carriers - Males and females equally affected - Often no previous family history (unless consanguineous) - Mutation may be homozygous or compound heterozygous
Examples of Autosomal recessive inheritance
CF Phenylketonuria (PKU)
Cystic Fibrosis (CF)
- Commonest autosomal recessive disease affecting Caucasians - ½, 500 - 250 babies a year - Carrier frequency = 1/25 - Mutations in CF transmembrane conductance regulator (CFTR) - Main defect – lungs and pancreas caused by thick mucus
Phenylketonuria (PKU)
- 1/10,000 - severe learning difficulties - epilepsy - treated by restricting phenylalanine intake - included in the UK new-born blood spot screening programme – as you can completely prevent all the effects by treating the condition
Mechanism in PKU
- loss of function - No phenylalanine hydroxylase so phenylalanine cannot be changed to tyrosine - Build-up of phenylalanine to toxic levels - Treat by avoiding phenylalanine in the diet (Both genetic and environmental disease)
X-linked (recessive) inheritance
- X chromosome - No male to male transmission - Predominantly affects males - Carrier females less severely affected (only 1 faulty copy and 1 normal copy) - Sometime affected females (Very rare)
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 to female transmission
X inactivation defn
one of the copies of the X chromosome present in female is inactivated; may be different in different cells
X inactivation eexplanation
- 2 copies of X chromosome in women
- only 1 needed
- 1 copy in every cell in every women – shutdown (condensed)
- X inactivation can affect severity of X linked diseases in girls
Examples of X linked inheritance
Recessive
- mainly affects males
- Haemophilia A + B = blood clotting disorders
Duchenne Muscular Dystrophy - chronic muscle wasting
Examples of X linked inheritance
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 (family tree)
- Patterns of inheritance can be more easily visualised
- 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
Approved Symbols
Which form of inheritance is most likely in this family?
Autosomal Dominant
- Equal number of male and women affected every generation
- In general, around 50% of children are effected
Which form of inheritance is most likely in this family
Answer = Autosomal recessive
- Male and females effected
Which form of inheritance is most likely in this family?
Answer = X linked recessive
- Only boys affected
Genetics Risk calculations in monogenic conditions
- Alice is 23 and is at university. Alice’s younger sister has CF. What’s the chance that Alice is a carrier?
We know Alice does not have CF so 3 possible options: so she’s either normal or carrier or carrier.
Answer = 2/3 chance that she’s a carrier
2. Alice’s younger sister has CF. What’s the chance Alice is NOT a carrier?
1 - 2/3 = 1/3
(2/3 from previous question)
- Alice’s younger sister has CF. What is the chance Alice will have a child with CF?
Answer = 1/150
for A to have a child with CF she must be a carrier so NM (2/3).
1/25 is the carrier rate for CF (him)
1/4 of offspring are normally affected by CF
- Alice’s younger sister has CF. What’s the chance Alice’s parents next baby will have CF?
Answer = 1/4
General question about how many offspring normally affected by CF
- Alice’s younger sister has CF. What’s the chance that her child will have CF?
Answer = 1/50
sister = 1
him = 1/25 (Carrier rate)
1/2 = half the children will be effected
complications to simple patterns of inheritance
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
- 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 (new incidence in family, not inherited)
- Recurrence risk in siblings is usually low
- No family history
- Risk increases with parental age
sporadic
new incidence in family, not inherited
Mosaicism
- Presence of more than 1 genetic subtype of genetically related cells
- Germline mosaicism in unaffected parent – apparent sporadic disease in child, may have a 2nd affected sibling
- Somatic Mosaicism in child – arises post fertilisation
e.g. mosaic monosomy 7
Mosaicism defn
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’s a mixed population of mitochondria (heteroplasmy)
- Maternally-inherited diabetes and deafness (MIDD)
- Leber hereditary optic neuropathy (LHON)
Mitochondrial Heteroplasmy
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
3 DNA bases (e..g CTG)
Anticipation
increasing severity of disorder in subsequent generations
Examples of Trinucleotide repeat disorders
- 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
Anticipation in myotonic 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 (100-159 genes) are expressed only when inherited from 1 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 14 (15q.1)
- mutation results in no gene expression at imprinted region
Prader Willi syndrome (PWS)
paternal 15q.1 chromosome is deleted since the maternal PWS region is inactive (imprinted)
- mental retardation, severe eating disorder, uncontrollable appetite, obesity, diabetes
Angelmanns syndromes (AS)
results when maternal 15q.q chromosome is deleted since the paternal AS gene (UBE3A) is inactive (imprinted)
- behavioural problems, mental retardation, hand flapping, absent speech, ataxia
Multifactorial Inheritance
- interaction between genetic and environmental factors
- cluster in families but incidence in close family members is <5%
Multifactorial inheritance due to
- genetic variation
- polygenic inheritance involving many different genes each with small additive effects
- Risk loci identified in GWAS
- Many common diseases including
- Asthma
- Obesity
- Cancer
- Rheumatoid arthritis
- Heart disease
- Schizophrenia
- Hypertension
- Type 1 diabetes
- Type 2 diabetes
- Multiple sclerosis
Summary of Topic 2
- Single gene disorders can be AD, AR or XL
- AD – can show reduced penetrance or be due to new mutations
- Trinucleotide repeat disorders can show anticipation
- Sex-specific inheritance 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
