Genetic diseases Flashcards
Describe the effect each mutation has on gene activity?
- Neural/silent
- Amorphic
- Hypomorphic
- Hypermorphic
- Neomorphic
What is epistasis?
- One gene affects the expression of another
- Compare Penetrance and expressivity.
- Why do we get same mutated gene but different phenotypes?
Penetrance is the proportion of individuals in a group with a given genotype that show the expected phenotype.
Expressivity is the degree to which a genotype is expressed in an individual.
What does fitness mean in terms of penetrance?
- Fitness: extent to which mutant allele carrying individuals produce off-spring
relative to those who do not carry a mutant allele
Why do 10% of people with retinoblastoma mutation never develop tumour?
- Reduced penetrance
The estimated penetrance of familial retinoblastoma is approximately 90%. If a man with familial retinoblastoma and mates with a woman who does not have the retinoblastoma mutation, what is the risk that their offspring will develop retinoblastoma?
The probability that the offspring will inherit the susceptibility allele is 0.50, as familial retinoblastoma is autosomal dominant.
* However, we need to consider the penetrance of the disorder.
* The probability of inheriting the disease causing allele (0.50) and expressing the phenotype (0.90) is given by multiplying the probabilities
* 0.50 x 0.90 = 0.45
What is multifactorial inheritance?
- Interaction of multiple genes (polygenic) with the exogenous (environmental) factors
- once you pass the threshold for disease you will get it - all or nothing
- if you are susceptible for disease/have specific risk factors the threshold is pushed back
How are autosomal dominant conditions inherited?
- If 50% of product (from non-mutant allele) is not enough for a cell/tissue to function – loss-of- function mutation in the gene produces a dominantly inherited phenotype.
Most dominantly inherited phenotypes are….
- Semi-dominant
- Individuals with 2 mutant alleles (homozygous) affected more severely than those with 1 mutant allele (heterozygous)
- Homozygous individuals: rare
In autosomal dominant inheritance what would you expect to see on a pedigree? (4)
- Successive generations affected – vertical transmission
- Males and females affected equally and with equal severity
- Males and females can transmit the mutant allele (1/2 Chance of inheritance)
- Affected individuals have affected parent
What is semi-dominance?
- Partially dominant trait
- Neither allele is completely dominant over the other, and the heterozygous individual exhibits a phenotype that falls somewhere between the two homozygous extremes.
- The phenotype of a heterozygote is distinct to (less severe?) the phenotypes of the homozygote phenotypes.
A male who has achondroplasia has children with a phenotypically normal female. If they have four children, what is the probability that:
a) None of their children will be affected with the disorder?
b) The probability that all four children will be affected?
- Autosomal dominant
- Affected homozygotes die early in life
- Therefore male parent is heterozygous and has 50% chance of passing on the mutant allele to each offspring.
a) Probability all four are unaffected (1/2)4 = 1/16 b) Probability all four are unaffected (1/2)4 = 1/16
What is codominance ?
Two alleles are expressed separately to give different traits in an individual
A man has neurofibromatosis type 1. His mother also has this condition.
a) What is the probability that his sister also has this disease?
b) In the absence of knowledge of his sisters phenotype, what is the probability that his sister’s daughter has neurofibromatosis type 1?
Mother has neurofibromatosis type 1, can be assumed to be heterozygous (homozygotes are rare and indeed none have been reported).
* The probability her daughter inherits the disease-causing allele is 1⁄2.
* The probability the sister transmits the disease-causing allele to her daughter is 1⁄2.
* The probability of both events occur is 1⁄2 x 1⁄2 = 1⁄4
* If we knew that they mans sister was affected, the probability that his sisters daughter is affected would be 1⁄2
What is dominant negative gene action?
- Occurs in diseases involving proteins forming oligomeric or polymeric complexes (proteins with more than 1 subunit)
- A mutant allele in a gene gives rise to a structurally abnormal protein, that interferes with the function of the normal allele in heterozygotes
How would you expect to see autosomal recessive inheritance on a pedigree?
- Disorder appears in one generation (not successive)
- Several children of one couple can be affected
- Affects males and females equally and with same severity
- Transmitted by phenotypically healthy parents (heterozygous carriers) – ‘skips’ generations
- Disorder in higher frequency in offspring of consanguineous couples (first cousin marriage)
What is Pleiotropy?
- Expression of an allele at one locus can have effects on 2 or more traits
e.g. Imagine a gene that, when mutated, not only affects the color of a person’s eyes but also has an impact on their height, hair texture, and susceptibility to certain diseases.
X-linked inheritance
No male-to-male transmission
* Females usually asymptomatic
- Sons and daughters have 50% chance of inheriting mutated allele from mother (heterozygous)
- Sons will express the disease
- Daughters do not express the disease
Describe X-linked recessive inheritance.
- Mostly affects males
- Females: Two copies of the mutant allele: disease phenotype
- Males: One copy of the mutant allele: disease phenotype
- Most affected males have unaffected parents
- Most often carrier mother
- No male-to-male transmission: Y chromosome from father
- For the children of III-6:
* What is the risk of a male child being affected?
* What is the risk of a female child being affected?
1- * III-6 is a female carrier, III-7 is an unaffected male
* Overallriskis1in4
* But:
* Sex dependent
* Son will have 1 in 2 risk
* Daughter has no risk (but 1 in 2 risk of being a carrier)
How does consanguinity between III-3 and III-4 alter the risk to their children?
- Both parents have mutant allele. 1 in 2 chance child is affected (irrespective of male/female)
- Son gains mutant allele from mother, daughters are homozygous (1 mutant will be silenced by X- inactivation)
How would you expect x-linked dominant inheritance to look on a pedigree?
- Each child of an affected parent has 1 in 2 chance of being affected
- Affected mother: 50% chance pass on mutant X allele to sons and daughters – same risk
- Affected father: risk changes depending on sex of child
- Sons unaffected – gain Y from father
- Daughters get mutant X from father
(see generation III)
What is mitochondrial inheritance?
- Purely maternal – most zygote mitochondria from oocyte
- No controlled segregation mechanism
- Mitochondrial DNA:
- Replicates independently of cell cycle
- Individual copies randomly distributed to daughter cells in mitosis
Describe heteroplasmy in relation to mitochondrial disease.
- Cell contains 10-100 mtDNA molecules
> Only some of the mtDNA contain a mutation – heteroplasmy - Normal mtDNA vs mutant mtDNA ratio varies in organs or in the course of successive cell divisions
= Patients with mitochondrial inherited disorders often report that individual symptoms change over time
How would mitchochondrial inheritance look on pedigree?
- Only females transmit the disease allele
- Complete penetrance shown here
> Heteroplasmy can result in incomplete penetrance (random distribution of mitochondria) - Common features:
- Reduced penetrance * Variable expressivity * pleiotropy
What are the 5 main causes of chromosomal abnormalities?
What are reciprocal and Robertsonian translocations?
- Reciprocal:
- Break point on two chr. mutual exchange of material
- No loss in genetic material (balanced translocation)
- Robersonian:
- Between acrocentric chr. where short arms lost, long arms fuse between 2 chr.
- Loss of short arm: no problems as usually contain genes for rRNA (multiple copies through genome)
- Have 45 chr. Phenotypically normal
(problems arise when u pass to children)
