Patterns of Single Gene Inheritence Flashcards
What is compound heterozygous?
What is hemizygous?
Compound heterozygous is that both alleles are mutated but the mutations are found in different parts of the gene.
Hemizygous - It generally just describes how males only have a single X chromosome. Regarding diseases, in males, having a mutated allele located on the X chromosome.
What is allelic heterogeneity?
It is where different mutations at the SAME locus cause a similar phenotype.
Example: a mutation in the same locus can lead to either nonfunctional CFTR or defective trafficking, both of which phenotypically present with severe Cystic fibrosis.
What is phenotypic heterogeneity?
different mutations in the same gene can lead to very different phenotypes.
It is a measure of severity.
What is locus heterogeneity?
Mutations in different chromosomal loci result in the same variant phenotype.
Example: long QT phenotype can be causes by mutations in more than one gene, potassium channels, sodium channels or structural proteins.
What is pleiotropy?
What is it the opposite of?
One gene affects multiple traits so having a single defect in this would result in affecting multiple organ systems, diverse phenotypes and a variety of signs and symptoms.
One trait affected by multiple genes is polygenic.
Sum up and contrast allelic, phenotypic, loci heterogeneity and pleiotropy
Allelic - different mutations in the same gene = one phenotype
Phenotypic - different mutations in the same gene = many different POSSIBLE phenotypes (basically the opposite of allelic, one phenotype vs many phenotype)
-still one mutation to one phenotype essentially
Locus heterogeneity: mutations on different genes = same phenotype
Pleiotropy: mutation of a single gene = many phenotypic effects.
What are 4 factors that confound pedigree inheritence?
- Early lethality of disorder - if someone who inherits this dies at an early age, it’d be difficult to know what their inheritence was.
- Small family size - may skew the conclusions because of chance
- Variable age of onset, decreased penetrance or variable expressivity.
- Non-mendelian inheritence
What are the characteristics of an autosomal recessive disorder?
What are the characteristics of a AR pedigree?
- You must have no Wild type allele and two mutated alleles (either same mutation of compound heterozygote), or hemizygotes
- mutant allele for AR disorders are rare, affect the function of enzymes and reduce or eliminate function of the gene product. (so usually loss of function mutations resulting in enzymes) - Parents are unaffected, asymptomatic carriers, the proportion of affected males to females is equal, the risk of giving birth to an affected is 1/4, the phenotype may not be found in parents but it is found in siblings of the affected.
Two heterozygous parents.
What is the risk that a child of either sex is affected?
What is the risk that a child of either sex is a carrier?
What is the risk that a child of either sex is unaffected?
What is the risk that an unaffected child is a carrier?
- 1/4
- 1/2
- 3/4
- 2/3
What does it mean to be an obligate heterozygote?
It means they must be heterozygous for the mutation. For example their offspring expresses an AR disease. The parents must be at least carriers.
Regarding AR diseases, a father is affected. We are unsure of the mother’s genotype. We know that she has an affected sister and both of her parents are unaffected. What is the chance the child will be affected.
So first what is the chance she is a carrier if she is unaffected? (you must exclude the probability she is affected)
2/3
What is the chance she would then donate the mutant allele?
1/2
2/3 x 1/2 = 1/3
What is carrier frequency and in what three situations that increase the inheritance for an AR disorder also have a high carrier frequency?
Consanguinity - closer than second cousins, increases the chance that both parents are carriers
Inbreeding - individuals from a small population mate with those from the same population
Genetic isolates - like geographically they were isolated and so carrier frequency may be higher for certain diseases. like Tay Sachs in ashkenazi jews
What are the features of an autosomal dominant pedigree?
- every affected individual has an affected parent and there is no skipping of generations.
- The number of males is equal to female and there is male to male transmission. (excludes X linked)
- 1/2 of offspring of an affected individual are affected.
- Normal siblings of affected individual goes on to produce normal offspring.
What is incomplete dominance?
If parents were heterozygous, what would be the risk that offspring of either sex will be affected?
Referring to AD mutations, those homozygous for the mutation will be more severely affect than the individual that is heterozygous
Example: achondroplasia, familial hypercholesterolemia
3 out of 4 (only bb is not affected).
For Pure AD inheritence, a parent that is bb and Bb
What is the risk an offspring of either sex will be affected?
What is the risk that a phenotypically normal child has the mutant allele?
BB homozygotes are exceedingly rare.
1/2
and no chance.
Autosomal dominant disorders can have two exceptions to Mendelian inheritance. What are they?
Reduced penetrance: if a person inherits a mutant allele and doesn’t express it (meaning it is not 100% of people who inherit it express it, then that is reduced penetrance)
Penetrance: probability that a mutant gene will have a phenotypic expression
-penetrance can also be age dependent.
Variable expressivity - people have the same genotype but can have varying severity of disease expression
What are sex-limited autosomal traits?
Genes are on both autosomes and the genetic mutations are present in both sexes however,
the phenotype is evident in only one sex. The mutation can be passed down by both sexes but it is a matter of expression.
What is male-limited precocious puberty?
It is an example of sex-limited AUTOSOMAL DOMINANT phenotype.
The mutation in the luteinizing hormone receptor leads to it being constitutively expressed.
Heterozygous males develop secondary sexual characteristics with a growth spurt by age 4. Females are carriers but not affected and their male children can be.
Again this is male to male transmission so instantly exclude X linked.
What is hemochromatosis?
It is a sex limited AUTOSOMAL RECESSIVE disorder.
It is the most common single gene inherited disease in America.
Phenotype: difficulty reducing excess iron. This is more common in males (5 to 10 times more likely.
This is because women via pregnancy and menstruation have natural ways to reduce iron levels.
What is achondroplasia
An autosomal dominant disorder with incomplete dominance. Patients have a short stature, short upper and lower extremities, proportionally large head,
A mother has an unaffected father and demonstrates achondroplasia (incomplete AD). Her husband is normal. What is the risk of the child being short?
She must be heterozygous because her father is normal so must be homozygous recessive. Therefore she has a 50% chance of donating either the normal or mutant.
answer: 50% risk.
Referring to X linked diseases, there is an unaffected male and a carrier female for Hemophilia A (XLR disorder)
what is the risk that females be carriers?
Risk that males will be affected?
For the above questions, what if affected male mated with unaffected, non carrier female?
Hemophilia A is X linked recessive
1/2 of females will be carriers
1/2 of males will be affected.
X linked dominant disorders are super rare.
2.
100% females would be obligate carriers
all males would be unaffected (inherit X from normal female.
NO MALE TO MALE TRANSMISSION IN X LINKED>
What is unbalanced X inactivation?
It refers to how a woman carrying the X linked recessive mutation can express it because of X inactivation.
Females are somatic mosaics (tissues may have different X’s inactivated.
What are the features of an X linked recessive pedigree?
No male to male transmission
The affected males far outnumber affected females.
heterozygous females are unaffected (although X inactivation)
Gene is transmitted from affected male to ALL daughters.