3.

4 – Genetics of Disease
Single gene disorders:
 A condition caused by a defect in a single gene (can be influenced indirectly by the
environment and other genes).
 Mutations causing single gene diseases have a major impact on the function of the
gene product, and are therefore rare.

Modes of inheritance:
 Autosomal dominant inheritance:
- only one of the two copies of the relevant gene need to be mutated to get the
disease.
- heterozygotes are affected by the disease (subject to penetrance of the mutation).
- penetrance = the extent to which a particular gene or set of genes is expressed in
the phenotypes of individuals carrying it, measured by the proportion of carriers
showing the characteristic phenotype.
- segregation = during gamete formation, the alleles for each gene segregate from
each other so that each gamete carries only one allele for each gene.
- expressivity quantifies variation in a non-binary phenotype across individuals
carrying a particular genotype.
- chances of passing on the mutation to offspring = 50%.
- e.g. achondroplasia (type of Dwarfism, mutation in FGF3), Huntington’s disease
(neurodegenerative disease), Marfan syndrome (defect in fibrillin – long fingers and
tall), familial breast cancer.

 Autosomal recessive inheritance:

- both copies of the relevant gene need to be mutated to get the disease.
- heterozygotes are unaffected carriers.
 - homozygotes are affected.
- chance of two carriers having an unaffected child = 25%.
- risk to siblings.
- consanguinity increases the likelihood of inheriting recessive traits as people in the
same family are more likely to have the same recessive alleles – more likely to be
heterozygotes (unaffected carriers) for the same conditions.
- e.g. cystic fibrosis, sickle cell anaemia, albinism (mostly).

Rachel and her parents cannot be

heterozygotes as they would not
have had children/be getting married,
therefore chance is 2/3.

 X-linked recessive inheritance:

- mother is a carrier (2 X chromosomes, one with a mutation), she is unaffected as
normal X chromosome acts as a backup.
- if she passes on the mutant one to a girl, the girl also has a backup X chromosome
that she inherits from her father so she is a carrier.
- if she passes on the mutant one to a boy, he inherits a Y chromosome from his
father, so has no backup X chromosome and is therefore affected – males are
hemizygous.
- risk to female offspring: 50% carrier, 50% normal.
- risk to male offspring: 50% affected, 50% normal.
- female carriers are usually unaffected, but it is possible that they are affected if
there is something wrong with the other X chromosome or if skewed (one X
chromosome is inactivated, it is usually random but can be preferential if there are
mutations).
- e.g. haemophilia, colour blindness, DMD (Duchenne muscular dystrophy).
- rare occurrence of X-linked diseases in females is due to their having two X
chromosomes and therefore having a backup chromosome – one X chromosome is
inactivated (the mutated one can be preferably inactivated).
 X-linked dominant inheritance:
- mother is affected, she has one mutant X chromosome and one normal one.
- if she passes on the mutant X chromosome to a girl then the girl will be affected but
due to X-inactivation will survive.
- if she passes on the mutant X chromosome to a boy then the boy only has a mutant
X chromosome and a Y chromosome from the father. He will probably die.
- risk to female offspring: 50% affected, 50% normal.
- risk to male offspring: 50% very severely affected/dead, 50% normal.
- e.g. Rett syndrome (second most common cause of mental retardation in girls),
hypophosphatemic rickets.

 Mitochondrial inheritance:
- mitochondrial heteroplasmy (different mitochondria have differences in their
genomes) – it is likely that most organisms house low levels of mitochondrial
variants. Over time, repeated mitotic segregation and clonal expansion can lead to
the mutant variants dominating the gene pool – this can lead to a threshold being
reached at which a mitochondrial disease will manifest.
- inheritance is maternal (in sperm, the mitochondria are in the tail which drops off).
- e.g. MERRF (myoclonic epilepsy and ragged red fibres), MELAS (mitochondrial
encephalopathy, lactic acidosis, stroke).

 Complex inheritance – uniparental disomy:

- usually, we have two copies of each chromosome (except sex chromosomes in
males), one from each parent.
- uniparental disomy refers to inheritance of 2 copies of one chromosome from one
parent and no copies from the other parent.
- some genes are imprinted, i.e. we only use the copy from one specific parent, if
that copy is not inherited we get the condition.
- e.g. Prader-Willi syndrome (need normal father’s chromosome not to get it, if two
copies of the maternal chromosome are inherited, it develops), Angelman syndrome
 (happy puppet syndrome, if both chromosome 15s are inherited from the father you
develop the syndrome).

Polygenic disease:
 Conditions which are not controlled by single genes, but are instead influenced by
many genes (as well as the environment, often).
 Mutations causing polygenic disease have a more moderate effect, and are therefore
relatively common.

 Susceptibility gene = gene that increases a person’s likelihood of contracting a

heritable illness.
 Polygenic trait characteristics:
- common (unlike single gene traits).
- multi-gene involvement – each gene has varying effects on trait occurrence and
development.
- often have major non-genetic influences i.e. environmental factors.
- unclear transmittance patterns.
 Congenital malformations showing polygenic/multifactorial inheritance:
- cleft lip/palate.
- spina bifida.
- clubfoot (talipes).
- congenital dislocation of the hip.
- congenital heart defects.
 Acquired diseases showing polygenic/multifactorial inheritance:
- asthma.
- autism.
- diabetes.
- epilepsy.
- ischaemic heart disease.
- hypertension.
- MS
- Parkinson’s disease.
- psoriasis.
- osteoarthritis.
- schizophrenia.

 Polygenic inheritance and the normal distribution:

- inheritance and expression of a phenotype may be determined by many genes at
different loci, with each one having a small additive effect.
 - additive = no gene is dominant or recessive to another, their effects are cumulative.
- characteristics show continuous distribution in the general population.
- this resemble a normal distribution.

 How do genes generate such a normal distribution?

Single gene trait. Polygenic trait.

 Conclusion: genes can generate a continuous trait when they act together.

 Discontinuous traits have a yes/no characteristic.

 The disease manifests once a certain threshold of susceptibility has been surpassed –
threshold model of susceptibility.

 Crossing the threshold requires a combination of the genes one has inherited and
the exposure one has had to environmental risk factors.
  - e.g. some people smoke 20 a day for 30 years and never get lung cancer (probably
have protective genes); some will get lung cancer after only 5-10 years of smoking.
 The siblings of an affected person have a higher liability:
- curve shifted to the right.

 Twin pair studies can be used to assess whether diseases have genetic components.
 1 in 89 deliveries are twins – 1/3 of these are monozygotic and 2/3 are dizygotic.

 Potential pitfalls of twin pair studies:

- MZ twins are the same sex whereas 50% of DZ twins are not – remedy by using
same-sex DZ twins.
- MZ twins are often treated differently to DZ twins, which could influence
behavioural traits – remedy by studying twins separated at birth (if there are
enough).
- intrauterine differences – MZ twins share more intrauterine tissues than DZ twins
during gestation, making it difficult to distinguish intrauterine environmental causes
from genetic causes.
- bias of ascertainment – people often focus on twins who have strikingly similar
behavioural traits but overlook those who don’t.

 Relative risk studies can also be used to assess whether a disease has a genetic
component.

Testing for susceptibility to multifactorial diseases:

 Various companies offer ‘genetic’ testing for susceptibility to diseases e.g.
Alzheimer’s, prostate cancer, breast cancer (excluding high risk genes), diabetes,
heart attack.
 Generally, these companies’ claims do not hold water – no good evidence that the
markers tested for predispose to disease.
 In some cases, it is possible the markers do give an indication.
 What are the implications of knowing you have genetic susceptibility to a disease?
- lifestyle choices – if the information is erroneous, this would be pointless.
- increased surveillance – increased radiation exposure (from imaging) with no good
grounds.
- risk-reducing surgery.
- insurance implications.
 With breast cancer, these companies do not test for BRCA1 mutations (increase risk
to 80%) but instead test for mutations in minor genes which would increase your risk
form 10% (population risk) to ~12%.
- giving people misinformation.

 Autism:
- multifactorial disease.
- severe neurodevelopmental disorder.
- 4-10 per 10 000, M>F.
- disorder of social interaction.
- poor communication, developmental delay, repetitive behaviours.
- part of a spectrum.
- seen as part of other syndromes – Fragile X.
 In 1997, there were reports of the MMR vaccine being associated with autism.
- 12 children only in the study.
- widespread media anger.
- vaccination levels fell in London to 50% by 2001.
- children affected with measles.
- boys rendered infertile by mumps.
- children born deaf and blind due to rubella in pregnancy.
- subsequent detailed research showed no causal link.
- researcher struck off by GMC.
 Genes and autism:
- MZ concordance = 80%, DZ concordance = 20%.
- familial recurrence risk = 2-6% (much higher than general population risk).
- several hundred families collected with >1 affected member.
- attempt to identify genes by linkage.
- few candidate genes identified.
- one that was identified is RELN (neuronal migration gene) – one of many.
 Benefits of genetic testing for autism:
- possibility of prenatal diagnosis and TOP (termination) for affected individuals.
- difficulty with predicting severity of condition – might terminate fetuses which
won’t be badly affected.
- possibility of preimplantation genetic diagnosis (PGD).