Inheritance Flashcards
What is a multifactorial condition
Disease that is due to a combination of genetic and environmental factors
Most common diseases are multifactorial
What are family studies
Compare the incidence of a disease amongst relatives of an affected individual with the general population
Family Studies
With risk for a multifactorial condition - fill in the gaps
- The risk of a condition in relatives of an affected individual is than the general population
Dramatically higher
What does proband mean
Individual affected with a disorder who is the first subject in a study (as of a genetic character in a family lineage)
What are the three ways of studying if a condition
has a genetic component
Family studies
Twin studies
Adoption studies
What does prevalence mean
How common a disease is in a given population
What does incidence mean
Onset of new cases in a given period of time
What are twin studies?
Compare genetically identical (MZ) with genetically non-identical (DZ) twins
What does concordance rate stand for?
% of twin pairs studies that both have the condition
Would expect it to be higher in monozygotic twins
Gives a rough figure for hereditability of a multifactorial disorder
What are adoption studies?
Adopted children of a parent with multifactorial condition have a higher risk of developing the disease
Higher in biological families only
Define hereditability
Proportion of the aetiology that can be ascribed to genetic factors as opposed to environmental factors
Expressed as a proportion of 1 or as a %
What is a way you can calculate hereditability
Concordance rate in monozygotic twins
Name the three characteristics of multifactorial inheritance
- The incidence of the condition is greatest amongst relatives of the most severely affected patients
- The risk is greatest for the first degree relatives and decreases rapidly in more distant relatives
- If there is more than one affected close relative then the risk for other relatives are increased
Define liability
When combine factors that influence the development of a multifactorial disorder, genetic and environmental
In the liability/threshold model which direction is the curve shifted in relatives compared to the normal population
Right
When the relationship is closer which direction does the curve shift in the liability/threshold model
Further to the right
What is the threshold marker in the liability/threshold model
Beyond this the abnormal phenotype is expressed
What is the definition for in the general population the proportion beyond the threshold (in the liability threshold model)
Population incidence
What is the definition for amongst relatives the proportion beyond the threshold (in the liability threshold model)
Familial incidence
What is the genome wide association studies
Utilises the fact genes can have several variants (alleles)
Compares the frequency of markers in a sample of patients and a sample of healthy controls
What would a pathogenic variation of a disease be
Variation in a gene which causes the gene to be inactivated or behave abnormally
Define polymorphisms
Genetic variation which still results in a functioning gene
What are the 4 environmental agents acting on embryogenesis
- Drugs and chemicals
- Maternal infections
- Physical agents
- Maternal illnesses
Name 4 post-natal environmental factors
- Type 2 diabetes - obesity
- Breast cancer - hormonal factors e.g. contraception
- Lung cancer e.g. smoking
- Schizophrenia e.g. recreational drugs
What is the 3 underlying principles of genetics are deduced by Mendel
- Segregation
- Dominance
- Independent assortment
What are the two types of mendelian inheritance
- Autosomal and sex-linked
- Dominant and recessive
What are the four types of non-mendelian inheritance
- Imprinting
- Mitochondrial inheritance
- Multifactorial
- Mosaicism
What are the three categories of genetic disorders
- Chromosome abnormalities
- Single gene disorders
- Multi-factorial and polygenic disorders
Define autosome
Any chromosome, other than sex chromosomes, that occurs in pairs in diploid cells
Define recessive
Manifest only in homozygotes
Define allele
One or more alternative forms of a gene at a given location (locus)
Define homozygous
Presence of identical alleles at a given locus
Homozygotes are affected
Define heterozygous
Presence of two different alleles at a given locus
Heterozygotes are unaffected and are usually referred to as carriers
Define allelic heterogeneity
Different mutations within the same gene result in the same clinical condition
What are the three typical features of autosomal recessive inheritance
Male and females are affected on equal proportions
Affect individuals only in a single generation
Parents can be related (consanguineous)
How can you calculate risk of carriers
Chance mother is a carrier x chance dad is carrier x risk of affected child if both carriers
Use population carrier frequency if risk is that of normal
Define consanguinity
Reproductive union between two relatives
Define autozygosity
Homozygosity by descent
e.g. inheritance of the same altered allele through two branches of the same family
In autosomal recessive conditions what are the chance of carrier parents having affected offspring
What are the chances of healthy siblings being carriers themselves
1 in 4
2 in 3
Define autosomal dominant inheritance
Disease manifest in the heterozygous state e.g. only one affected gene needed
What are the 3 typical features of autosomal dominant inheritance
- Males and females are affected in equal proportions
- Affected individuals are seem in multiple generations
- Transmission by individuals of both sexes, to both sexes
Define penetrance
The percentage of individuals with a specific genotype showing the expected phenotype
Define expressivity
Refers to the range of phenotypes expressed by a specific genotype
In autosomal dominant inheritance what is the recurrence risk
50% for transmission of the mutation
Dependant on penetrance and expression
Define anticipation
Genetic disorder affects successive generations earlier or more severely, usually due to expansion of unstable triplet repeat sequences
Define somatic mosaicism
Genetic fault present in only some tissues in the body
Define gonadal (germline) mosaicism
Genetic fault present in gonadal tissue
Define late-onset
Condition not manifest at birth (congenital), classically adult-onset
Define sex-limited
Condition inherited in the autosomal dominant pattern that seems to affect one sex more than another
Define predictive testing
Testing for a condition in a pre-symptomatic individual to predict their chance of developing a condition
What is the only mode of transmission where male to male transmission is seen?
Autosomal inheritance
Define x-linked inheritance
Genes carriers on the X chromosome
What are the three typical features of X-linked inheritance
- Usually only male affected
- Transmitted (usually) through unaffected females
- Female carriers can be affected to lesser degree - No male-male transmission
Define lyonization (X inactivation)
Generally only one of two X chromosomes active in each female cell. Can be skewed
Can an infected male in X-linked inheritance have an affected son
An affected male cannot have an affected son
But all daughters will be carriers
Define genomic imprinting
Epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner
Define epigenetic
Non-genetic influence on gene expression
Define homoplasmy
A eukaryotic cell whose copies of mitochondrial DNA are all identical (identically normal or have identical mutations)
Define heteroplasmy
Multiple copies of mtDNA in each cell
Can vary between cells in the same tissue or organ and organ to organ in the same person and between individuals of the same family
What are the 4 factors of mitochondrial genetic disease
Group of disorders caused by dysfunctional mitochondria
Caused by mutations in the mitochondrial DNA (15%)
Caused by mutations in nuclear genes, whose gene products are imported into the mitochondria
Acquired conditions caused
What is the carrier frequency of sickle cell disease (haemochromatosis)
1/10
What is the carrier frequency of cystic fibrosis
1/25
Name some autosomal recessive conditions
Haemochromatosis (sickle cell disease)
Cystic fibrosis
Congenital adrenal hyperplasia
Connexin-26 (deafness)
Tay-Sachs disease
MCAD disease
Spinal muscular atrophy
Friedreich’s ataxia
Hurler syndrome
Ataxia telangiectasia
Describe cystic fibrosis
Commonest AR condition affecting northern European population
Chronic condition mainly affecting lungs and guts - variable presentation
Incidence - 1 in 2500
CFTR gene on 7q31.2
F508 commonest mutation (80%)
What is the sweat test
Diagnostic test for cystic fibrosis
Not genetic marker
If someone in a parents genetic line has an autosomal condition what is the equation for risk to there child (if neither have been tested)
Parent with genetic line = 1/2 (chance a carrier)
Parent b = 1/25 (population carrier frequency)
Risk of affected child if both carriers = 1/4
1/2 x 1/25 x 1/4 = 1/200
Autosomal recessive
One parent + one parent - equation
Chance parent a = 1
chance parent b = 1/250 (test only detects 90% mutations)
risk of affected child if both carriers = 1/4
1/1000
What is the phenotype correlation in cystic fibrosis of genotype F508
Pancreatic insufficiency and chronic lung disease
What is the phenotype correlation in cystic fibrosis of genotype R117H
Majority are pancreatic sufficient but have chronic lung disease
What is an example of x-linked inheritance
Haemophilia
What is an example of multifactorial inheritance
Cleft lip and palate
Combination of both genetic and environmental factors
