Patterns of Single Gene Inheritance Flashcards
What are the Mendelian patterns of inheritance?
- ) Autosomal Recessive
- ) Autosomal Dominant
- ) X-linked recessive
- ) X-linked dominant
What are the three exceptions of Mendelian patterns of inheritance?
- ) Reduced penetrance
- ) Variable Expressivity
- ) Sex-limited phenotypes
Determined primarily by an allele at a single chromosomal locus
-Caused by mutations that occur at a specific location on a locus
Single gene disorders
Single gene disorders are the result of a mutation at a specific locus on the chromosome. These mutations occur on a specific gene and result in a different
Phenotype
One of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome
Allele
Set of alleles present at a single locus
-refers primarily to the autosomes
Genotype
Observable expression of the genotype
Phenotype
When the two alleles are the same (i.e. both WT or both mutant)
Homozygous
When one allele is WT and the other allele is a mutation
Heterozygous
When both alleles are mutant, but the mutation are at different locations in the gene
Compound heterozygotes
When an abnormal gene is located on an X chromosome in a male patient
Hemizygous
Distinct mutations in the same gene producing the same phenotype
Allelic Heterogeneity
Distinct mutations in the same gene producing very different phenotypes
Phenotypic heterogeneity
Descibes different mutations in the same gene that can sometimes give rise to strikingly different phenotypes
Phenotypic Heterogeneity
When mutations in more than one gene can cause the same disease
-Ex: Long QT syndrome can be cause by mutations to sodium channels, potassium channels, or structural proteins
Locus Heterogeneity
One gene that affects multiple traits
-Ex: Von Hippel-Lindau Syndrome
Pleiotropy
A single gene defect that affects multiple organs, produces multiple diverse phenotypes, and results in a variety of signs and symptoms
Pleiotropy
When multiple genes affect one trait
-Ex: Hair loss
Polygenic
Mutations at different loci that produce the same phenotype
Locus Heterogeneity
Affect 1:300 neonates and are responsible for 7% of pediatric hospitalizations
Single gene disorders
Most single gene disorders follow a pattern of
Mendelian Inheritance
Follow classic inheritance patterns and occurs in fixed and predictable proportions among offspring of specific types of matings
Mendelian Diseases
For Mendelian diseases, you can predict the pattern of inheritance and the genotype from the
Pedigree
Used to establish the pattern of transmission of single gene disorders
-Determined from the family history
Pedigrees
Can establish a pattern of inheritance and can be used to determine the degree of risk of disease for family members
Pedigrees
Early lethality of disorder, small family size, variable age of onset, and non-Mendelian inheritance can all
Confound pedigree interpretation
If the disease occurs early after birth, or during pregnancy,
Early lethality
The pattern of inheritance of single gene disorders is determined by what two factors?
- ) Whether phenotype is dominant or recessive
2. ) Chromosomal location of gene locus
Does not follow Mendelian inheritance
Mitochondrial Genome
Most of the time when we are talking about mutations in the sex chromosomes, we are talking about mutations on the
X-chromosome
Y mutations are very rare
An individual must have two mutant alleles and no wild type in order to have an
Autosomal Recessive (AR) Disease)
In an AR disease, the type of mutation in each allele CAN be different, i.e. you could be a
Compound Heterozygote
Reduce or eliminate function of the gene product
- Often affect the function of enzymes
- are RARE
AR Diseases
Cystic fibrosis is a common representative of an
AR disease
For an AR disease, the risk that a child will inherit the disorder is
25%
For an AR disease, the risk that a child will be a carrier is
50%
For an AR disease, the risk that a child will be an unaffected carrier is
2/3 (had to delete the affected)
In an AR pedigree, the parents are
Unaffected asymptomatic carriers
For an AR pedigree, what is the difference between number of affected males and females?
Affected males = # affected females
The more rare or unusual a trait is in a population, the more likely that the parents are
Related
Wilson’s disease is an example of an
AR disease
New mutations are VERY
Rare
Not typically the right answer choice
What factors can affect the risk of inheritance for an AR disorder?
- ) Carrier frequency
- ) Consanguinity
- ) Inbreeding
- ) Genetic Isolates
Increases the chance that both parents are carriers of the same mutant allele
-When second cousins or closer mate
Consanguinity
When individuals from a small population choose mates from the same population
Inbreeding
When certain races are more likely to develop a disease
-Ex: risk of Tay-sachs disease in Ashkenazi Jews (the carrier frequency is 10X higher than in other European populations)
Genetic Isolates
Deposition of cholesterol in the tendons
Xanthoma
Makes up more than 50% of known Mendelian disorders
- Only one mutant allele is required for disease
- Ex: Familial Hypercholesterolemia
Autosomal Dominant (AD) Disease
The incidence of disorders can be high, especially in some populations, for
AD Diseases
In general, BB homozygotes are exceedingly
Rare
If an affected heterozygote (Bb) of an AD disease mates with an unaffected homozygote (bb), what is the chance that a child of either sex will be affected?
50%
What is the risk that a phenotypically normal child has the mutant allele for an AD disease?
Zero (unless there is incomplete penetrance)
Do not skip generations (i.e. ever affected individual has an affected parent)
AD Pedigrees
For an AD pedigree, what is the difference between number of affected males and females?
Affected males = # affected females
For an AD pedigree, male-to-male transmission does occur, and a male can have an unaffected
Daughter
For an AD pedigree, unaffected individuals will have
Unaffected Children
Most AD disorders display
Incomplete dominance
Implies that an individual that is HOMOZYGOUS for the AD mutation will be more severely affected than an individual who is HETEROZYGOUS
Incomplete dominance
What are two clinical examples of incomplete dominance?
Achondroplasia and Familial Hypercholesterolemia
Means that all genotypes, homozygous or heterozygous, display the same phenotype
Complete Dominance
What are two AD traits that create exceptions to the Mendelian Rules?
Reduced penetrance and Variable Expressivity
When discussing the probability that a mutant gene will have ANY phenotypic expression at all. If the probability is less than 100%, then the gene has
Reduced penetrance
A phenotype can have age dependent
Penetrance
When all individuals with the disease ARE affected, but the severity (phenotype) of the disease differs in people who have the same genotype
Variable expressivity
Penetrance is considered to be “all or none” in the sense that if 100% of the people have the phenotypic expression, then the gene has complete penetrance, but anything less than 100% is
Reduced (Incomplete) Penetrance
An example of reduced penetrance is the AD form of split hand foot malformation, which has a reduced penetrance of
70%
What is an example of a disease that has an age dependent penetrance and variable expressivity?
Neurofibromatosis
Can make a pedigree difficult to interpret because the disease may appear to skip a generation
Reduced Penetrance
Genes occur on the autosomes and the mutations are present in BOTH sexes, but the phenotype is evident only in one sex
Sex-linked autosomal traits
The genes for the trait can be carried and transmitted by the opposite sex, although it is NOT displayed in that sex because of anatomical or physiological differences
Sex-linked autosomal traits
What is the best characterized Sex-linked AD disorder?
Male-limited precocious puberty
Mutation in lutenizing hormone receptor gene (LHR), which results in LHR being “on” all the time
-Only expressed in males
Male-limited precocious puberty
Males affected with Male-limited precocious puberty develop secondary sexual characteristics w/ a growth spurt by the age of
4
In a pedigree, male-to-male transmission (i.e. dad passes disease to son) excludes
X-linked disorder
What is the most well documented sex-limited AR disorder?
-Most common single-gene inherited disease in the US
Hemochromatosis
More common in males (5-10x) who have no physiologic process to reduce excess iron
-In women, pregnancy and menstruation reduce iron levels (10-20% incidence of males)
Hemochromatosis
How many genes are there on the x-chromosome associated with disease phenotype?
300
The dominant and recessive patterns of X-linked inheritance depends on the phenotype in
Heterozygous women
You can have a female who is heterozygous for an X-linked disorder still display the phenotype because of
X-inactivation
When discussing X-linked recessive (XLR) disorders, males are referred to as being
Hemizygous (XY)
When a woman heterozygous for an XLR disorder mates with an unaffected male, what are the odds for the male and female children of being affected?
- ) 1:2 Risk that males will be affected
2. ) 1:2 risk that females will be carriers
For an XLR, what are the odds if the male is affected but the female is unaffected?
- ) All females will be carriers
2. ) All males are normal
What are the characteristics of an XLR pedigree?
- ) Males are affected more than females
- ) Heterozygous females are unaffected (depending on X-inactivation)
- ) Gene is transmitted from affected male to ALL daughters
In an X-linked dominant (XLD) disorder, the trait is NEVER passe from the father to the
Son
In an X-linked dominant (XLD) disorder, if an affected male and a normal female have kids, all the daughters are
Affected
What is a characteristic of XLD disorders?
More females are affected than males
Presence in an individual of at least two cell lines that differ genetically (due to a mutation) but are derived from a single zygote
-An exception to Mendelian inheritance
Mosaicism
What are the two types of mosaicism?
- ) Pure somatic (occurs in somatic cells)
2. ) Pure germline (mutation occurs in germ cells)
When parents who are phenotypically normal and who test negative for being a carrier have more than one child affected with a highly penetrant AD or XLR disorder, we suspect
Germline Mosaicism
What are three examples of germline mosaicism?
Osteogenesis imperfecta, Hemophilia A and B, and Duschenne muscular distrophy
Very rare in AR, but are a common cause of some diseases
- probability is 10^-6 to 10^-7 per gamete
- another cause for divergence from Mendelian inheritance
New Mutations
Diseases that are produced by dominant alleles with effects so severe that persons with them do not have children (genetic lethal), are typically only observed when there are
New Mutations
When looking at pedigree, if thing seem to REALLY not make sense, it is possible that there has been
Mis-attributed paternity
Says that genes originating from maternal and paternal genomes are equally expressed in the offspring
Mendel’s Law
What is a clear violation of Mendel’s law?
-Affects about 100 human genes located on select chromosomes
Genomic imprinting
When the maternal allele is methylated and the methylated gene is NOT expressed
Maternal imprinting
Nearly all mutations that create enzyme deficiency and matabolic disease are
-Because a single defective allele will only reduce function by 50%
Recessive
What are the three major routes to dominance?
- ) Gain-of-function
- ) Haploinsufficiency
- ) Dominant-negative effect
Mutation allows protein to function in ways not possible for the normal gene product.
Example: constitutive activity of ras, can be produced by amino acid substitutions that reduce GTPase activity, so that ras is always active, not just when growth factors bind receptors.
Gain-of-function
When one functional allele cannot provide sufficient product for normal function.
Ex: 50% of normal protein C activity is not sufficient to prevent risk of thrombosis
Haploinsufficiency
Created by nonsense, frameshift, or splicesite mutations that block production of any protein by the mutant allele
Haploinsufficiency
If the active form of the protein is an oligomer, a single defective subunit can block function of the entire protein. This is an example of the
Dominant-negative effect
The transcription factor p53 is a tetramer. Mutations that block DNA-binding by one of the four subunits can prevent function of the tetramer, leading to the
Dominant-negative effect
