T1: Genetics disease - Categories, Inheritance Patterns and Impacts Flashcards
What is the role of genetic and environmental factors in multifactorial conditions such as congenital abnormalities, cancer, diabetes and psychiatric illness?
For any condition the balance of genetic and environmental factors can be represented by a point somewhere within the triangle of 100% environmental, single gene and polygenic.
Scurvy has is very far towards environmental factors, whereas Duchenne muscular dystrophy is at the other end, affected mostly by genetics.
How are genetic disorders classified?
- Multifactorial / Complex: the interaction of multiple genes (genetic predisposition) in combination with environmental factors e.g. type II diabetes, ischemic heart disease.
- Single gene: a mutation in a single gene = Mendelian inheritance – AD, AR, XL e.g. cystic fibrosis
- Chromosomal: an imbalance or rearrangement in chromosome structure e.g. aneuploidy, deletion, translocation
• Mitochondrial: a mutation in mitochondrial DNA
Somatic mutations: mutation(s) within a gene(s) in a defined population of cells that results in disease e.g. breast cancer
What are the modes of single gene inheritance?
- Autosomal Dominant
- Autosomal Recessive
- X-Linked
How is AD disorders inherited? What is the pattern we see in family history?
- A trait or disease runs from one generation to the next
- Males and females equally affected
- Offspring of affected person has a 50% (1 in 2) chance of inheriting the mutation
AD disorders such as Huntington’s, Marfans syndrome, often affects structural proteins, receptors, transcription factors. Chromosome deletions and duplications can be inherited as well in an autosomal dominant manner. For example a Chromosome deletion such as 22q11 deletion syndrome is a genetic syndrome known as DiGeorge’s syndrome. Affected individuals are described as heterozygous for the mutation.
AD disorder show a VERTICAL pattern of inheritance.
What is penetrance?
Penetrance: The frequency with which a specific genotype is expressed by those individuals that possess it, usually given as a percentage.
• May alter with age e.g. Huntington disease by 80 years 100% penetrance penetrance
Incomplete penetrance – not all relatives who inherit the mutation develop the disorder – e.g. BRCA1 mutations 80% life time chance of developing breast cancer
What is expressivity?
Expressivity: - variation in expression - the extent to which a heritable trait is manifested by an individual.
• Marfan Syndrome: the phenotype ranges from aortic dilatation to lens dislocation to stretch marks
BRCA1 mutation - +/- ovarian cancer, breast cancer
What is the term used to describe this definition:
“The symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next. In most cases there is an increase in the severity of symptoms too. “
Anticipation.
Examples include:
- Myotonic dystrophy
- Huntington’s disease
What is the term used to describe this definition:
“New mutation that has occurred during gametogenesis or in early embryonic development.”
de novo mutation
Give details of AR inheritance.
Autosomal Recessive Inheritance (AR)
• Disease seen in one generation
• Does not tend to pass from one generation to next – parents usually unaffected
• Offspring of affected individual has low risk of disease – unless in consanguineous relationship
• Relatives may be asymptomatic carriers of the disease
• Affects males and females equally
Gene mutations, not chromosomes
What pattern is seen in family history in AR inheritance?
Horizontal
What is X-Linked inheritance?
• The mutation is found on the X chromosome
• Males affected
• Females may be unaffected, mildly through to fully affected
• Males usually more severely affected than females
• Can NOT have male to male transmission - it is due to mutation on the X linked chromosome. When he has a son, he has passed on his Y chromosome.
• Shows a DIAGONAL pattern of inheritence
• Gene mutations and chromosome deletions/ duplications
Examples include:
Duchenne Muscular dystrophy, Fragile X syndrome, Red / green colour-blindness and Haemophilia.
Why can females have a variable phenotype in X-linked inheritence?
Most XL carrier females are asymptomatic or have mild symptoms. However they can have significant symptoms. Two main factors influencing expression of phenotype:
- X inactivation
- XL domination vs XL recessive inheritance
Often we cannot predict a female phenotype accurately on prenatal testing
What is X-inactivation?
This is a normal process. It is the process of the random inactivation of one of the X chromosomes in cells with more than one X chromosomes. Compensates for the double dose of X gene dose. Occurs very early in embryogenesis. Once inactivated an X-chromosome remains inactive throughout the lifetime of the cell and its descendent. Most, but not genes are switched off during inactivation.
How does X-inactivation affect disease expression?
Approximately 50% of cells express the normal gene. However there can be:
- Skewed X-inactivation – random preference for “normal” X chromosome to be inactivated – significant phenotype. It occur in at different levels and different tissues.
- Tissue variability – random preference for the X chromosome with the mutation to be active in crucial tissue group – e.g. muscle in Duchenne Muscular dystrophy
What are the two types of X-Linked inheritance?
XL dominant (rare) and XL recessive.
In XL recessive, you require both copies of the XL mutation. If there is skewed X-inactivation, some of the carrier females may have some symptoms.
The dominant conditions are much rarer. Rett syndrome is due to a mutation on the X chromosome. If a male has one of the mutations in his single X chromosome, the pregnancy will not survive. Females are the only people which can have Rett’s syndrome. The other X is unaffected that protects them enough so that they can be born. It is a developmental disorder.
In some of the dominant conditions boys can be born and through X inactivation, women have milder symptoms.
