Inheritance Patterns Flashcards
Categories of Genetic Disorders
• Chromosome abnormalities
• Single gene disorders
• Multi-factorial and polygenic disorders e.g. spina bifida, cleft lip and palate
Mendel Deduced the Underlying Principles of Genetics
- Segregation
- Dominance
- Independent assortment
Dominance
Every gene has 2 alleles that code for a trait
In heterozygotes, one allele is dominant meaning it will always show, one is recessive and is masked by the dominant allele
Segregation
Allele pairs separate/segregate randomly from each other during meiosis – each cell has a single allele for each trait
Independent Assortment
Traits are transmitted to offspring independently of one another
Mendelian Inheritance
• Autosomal and sex-linked
• Dominant and recessive
Non-Mendelian Inheritance
• Imprinting
• Mitochondrial inheritance
• Multifactorial
• (Mosaicism)
Autosome
Any chromosome, other than the sex chromosomes (X or Y), that occurs in pairs in diploid cells
Recessive
Manifest only in homozygotes
Allele
One or more alternative forms of a gene at a given location (locus)
normal allele is also referred to as wild type
disease allele carries the pathogenic mutation
Homozygous
Presence of identical alleles at a given locus
homozygotes are affected
Heterozygous
Presence of two different alleles at a given locus
Heterozygotes are unaffected and are usually referred to as carriers
Allelic heterogeneity
The situation where different mutations within the same gene result in the same clinical condition e.g. cystic fibrosis.
Thus an individual with an autosomal recessive condition may be a compound heterozygote for two different mutations
In autosomal recessive inheritance the disease manifest in the homozygous state I.e “double-dose” of affected alleles.
Typical features include
Male and females affected in equal proportions
Affected individuals only in a single generation
Parents can be related, i.e. consanguineous
Consanguinity
Reproductive union between two relatives.
Autozygosity
Homozygosity by descent, i.e. inheritance of the same altered allele through two branches of the same family.
Summary (ARI)
Double-dose of same altered gene required to cause problems
· Carrier parents have no health problems themselves, but have 1 in 4 offspring risk
· Healthy siblings have a 2 in 3 chance of being carriers themselves
· AR conditions can affect any family, but more common in consanguineous unions
· Some AR conditions are more common in certain ethnic groups
Autosomal Dominant Inheritance
Disease manifest in the heterozygous state, i.e. only one affected gene needed
Typical features include
Male and females affected in equal proportions
Affected individuals in multiple generations
Transmission by individuals of both sexes, to both sexes
sometimes both parents are unaffected, this can be for three reasons: most commonly they don’t have the genes for it, gonadal mosaicism or SOMETIMES the mother has REDUCED PENETRANCE or VARIABLE EXPRESSION i.e. disease is there but not expressed clearly.
Only one defective gene needed. 50% chance of offspring having condition (1 affected and 1 unaffected parent). Example. Huntington’s disease. ONLY WAY TO PASS ON DISEASE FROM MALE TO MALE. Thus if you see male-male transmission, MUST BE AUTOSOMAL DOMINANCE INHERITANCE
Penetrance & variability
Penetrance
The percentage of individuals with a specific genotype showing the expected phenotype
• Complete: gene or genes for the trait are expressed in all the population
• Incomplete: the genetic trait is only expressed in parts of the population
Expressivity
Refers to the range of phenotypes expressed by a specific genotype
I.e will the disease be expressed more harshly in certain people, will the disease affect at a certain age
Recurrence risk
50% for transmission of mutation
BUT will the person be affected?
Depends on penetrance and expression
New mutation
Example – Neurofibromatosis type 1, up to 50% of cases occur as result of de novo mutation
Anticipation
Whereby genetic disorder affects successive generations earlier or more severely, usually due to expansion of unstable triplet repeat sequences
Example – Myotonic Dystrophy
Somatic Mosaicism
Genetic fault present in only some tissues in body.
Gonadal (germline) Mosaicism
Genetic fault present in gonadal tissue (reproductive tissue)
-Does not affect the individual with the Germline mosaicism health
Late-onset
Condition not manifest at birth (congenital), classically adult-onset
Example – Hypertrophic Cardiomyopathy
Sex-limited
Condition inherited in AD pattern that seems to affect one sex more than another
Example – BRCA1/2
Predictive testing
Testing for a condition in a pre-symptomatic individual to predict their chance of developing condition
Summary (ADI)
Disease manifest in the heterozygous state, i.e. only one affected gene needed
· Male and females affected in equal proportions
• Affected individuals in multiple generations
• Transmission by individuals of both sexes, to both sexes
• Only MOI with male-to-male transmission
• penetrance, variability
X-linked Inheritance
Genes carried on X chromosome
Caused by a mutation in genes on the X-chromosome
Typical features
Usually only males affected
Transmitted (usually) through unaffected females
No male-to-male transmission
Eg; haemophilia and duchenne muscular dystrophy
• X-linked can never be passed from father to son (NO MALE-TO-MALE TRANSMISSION - BECAUSE SONS ALWAYS GET THEIR X CHROMOSOME FROM THEIR MOTHER) - all sons from affected male and unaffected female are unaffected
• All daughters from an affected male are CARRIERS all sons are UNAFFECTED
• Males can NEVER be carriers
• Usually only males are affected
• Transmitted (usually) through unaffected females
• X-linked dominant example is Alport’s syndrome (kidneys)
• X-linked recessive example is Duchenne’s muscular dystrophy
Lyonization (X inactivation)
Generally only one of two X chromosomes active in each female cell. Can be skewed
As baby girls are developing one of the X chromosomes are switched off- 50% of the genes inherited from mother switched off and 50% inherited from father switched off
• LYONISATION: The process of X chromosome inactivation
• One of the two X chromosomes in every cell in a female is randomly inactivated early in embryonic development.
• X chromosome inactivated to prevent female cels having twice as many gene products from the X chromosome as males
• Only one functional copy of X chromosome
XL inheritance summary
· Genes carried on X chromosome
· Usually only males affected, but female carriers can be affected to lesser degree
• Transmitted (usually) through unaffected females
• No male-to-male transmission
• An affected male cannot have affected sons, but all his daughters will be carriers
Genomic imprinting
An epigenetic (non-genetic influence on gene expression) phenomenon that causes genes to be expressed in a parent-of- origin-specific manner
For some genes only 1 out of the 2 alleles is active, the other is inactive. For particular genes it is always the paternal or the maternal allele
Homoplasmy
a eukaryotic cell whose copies of mitochondrial DNA are all identical (identically normal or have identical mutations)
Heteroplasmy
there are multiple copies of mtDNA in each cell
•the name given to denote mutations which affect only a proportion of the molecules in a cell
•the level of heteroplasmy can vary between cells in the same tissue or organ, from organ to organ within the same person, and between individuals in the same family
Mitochondrial genetic disease
Group of disorders caused by dysfunctional mitochondria
Caused by mutations in the mitochondrial DNA (15%)
Caused by mutations in the nuclear genes, whose gene products are imported into the mitochondria
Acquired conditions caused by e.g. drugs
Who is mitochondrial DNA (mtDNA) inherited from?
The mother
