Patterns of Single Gene Inheritance Flashcards
Locus definition:
- physical site or location of a specific gene on a chromosome
- two alleles for each locus (one each on each parental chromosome)
Genotype definition:
- set of alleles present at a single locus
Phenotype definition:
- observable expression of the genotype
- Can be:
- biochemical
- cellular
- physical (clinical)
Single gene disorders are:
- diseases caused by mutations in a single gene.
- significant disease burden on society, especially in neonates and pediatrics
Homozygous definition:
- both alleles are the same
- i.e. both wild type or both mutant
Heterozygous definition:
- one allele is wild type
- one allele is mutant
Compound heterozygous definition:
- both alleles are mutant, but mutations on each chromosome are at different parts of the gene
- ex: cystic fibrosis
Hemizygous:
- abnormal gene is located on chromosome X
- note: male patients only have a single X chromosome (XY)
Allelic heterogeneity definition:
- DIFFERENT MUTATIONS IN THE SAME GENE result in the SAME clinical phenotype
Phenotypic heterogeneity definition:
- DIFFERENT MUTATIONS IN THE SAME GENE result in VERY DIFFERENT clinical phenotypes
Locus heterogeneity definition:
- MUTATIONS IN DIFFERENT GENES (at distinct loci) CAN result in the SAME CLINICAL PHENOTYPE
Mendelian diseases:
- follow one of four classic inheritance patterns
- occur in fixed and predictable proportions in offspring
Pedigrees are used to:
- establish the pattern of inheritance of single gene disorders
- determine degree of risk of disease in offspring
determined by family history
Four factors that can confound pedigree interpretation:
- early lethality of disorder
- small family size
- variable age of onset; decreased penetrance or variable expressivity
- non-Mendelian inheritance
Male pedigree symbol:
square
Female pedigree symbol:
circle
The two factors that determine pattern of inheritance of single gene disorders:
- whether phenotype is dominant or recessive
- chromosomal location of gene locus
- autosome
- sex chromosome (X or Y)
- mitochondrial genome
Does the mitochondrial genome follow Mendelian inheritance?
- No
- always inherited from mother
What are the four major patterns of Mendelian inheritance?
- autosomal recessive
- autosomal dominant
- X-linked dominant (very rare)
- X-linked recessive
Autosomal recessive disease genotype:
- must have two mutant alleles and no wild type
- the type of mutation in each allele can be different (i.e. compound heterozygote)
- rare
Effect of mutant alleles in autosomal recessive disorders:
- reduce or eliminate function of gene product
- often affect enzyme function
What type of inheritance is this?
(b is mutant allele)
autosomal recessive
- bb has disease phenotype
Risk that a child of either sex will be affected in autosomal recessive inheritance:
1/4 (25%)
Risk that a child of either sex will be a healthy carrier in autosomal recessive inheritance:
1/2 (50%)
Risk that a child of either sex will not be affected in autosomal recessive inheritance:
3/4 (75%)
Four factors that affect the risk of inheritance of a autosomal recessive disorder:
- carrier frequency (how prevalent carriers are)
- consanguinity (closely related)
- inbreeding (small population)
- genetic isolates
What are the five key features of an autosomal recessive pedigree?
- parents unaffected carriers
- males = females
- recurrence risk to unborn sibling of an affected individual is 25%
- phenotype found in siblings
- rare trait = likelihood of consanguineous mating
What type of inheritance is this?
(B is mutant allele)
autosomal dominant
only need one copy of mutant allele to have phenotype
Risk that a child of either sex will be affected in autosomal dominant inheritance:
1/2 (50%)
Autosomal dominant disease genotype:
- only need one mutant allele to have phenotype
What type of pedigree is this?
autosomal recessive
- parents are unaffected carriers
What type of pedigree is this?
autosomal dominant
- every affected individual has an affected parent
- no skipping of generations
Four features of autosomal dominant pedigree:
- every affected individual has an affected parent; no generation skipping.
- males and females equally affected.
- about 1/2 of offsprign of affected individual affected.
- normal siblings of affected individuals have all normal offspring.
In what Mendelian inheritance pattern can male-to-male transmission occur?
autosomal dominant
Incomplete dominance definition:
- a form of autosomal dominant inheritance
- individual homozygous for autosomal dominant mutation will be more severely affected than individuals heterozygous for autosomal dominant mutation
- note: homozygous AD mutations are rare
What type of inheritance is this?
(B is mutant allele)
incomplete dominance
- BB more severely affected than Bb
Risk that a child of either sex will be affected in incomplete dominance inheritance:
- 3/4 (75%)
- a form of autosomal dominant inheritance
How do you determine whether an X-linked inheritance is dominant or recessive?
- look at phenotype in heterozygous woman
- no phenotype = recessive
- phenotype = dominant
What type of inheritance is this?
(Green X is mutant allele)
X-linked recessive inheritance
(female carrier parent)
- offspring females 1/2 chance of carrier
- offspring males 1/2 chance of affected
What type of inheritance is this?
(Green X is mutant allele)
X-linked recessive inheritance
(affected male parent)
- all female offspring carriers (obligate)
- all normal male offspring
What type of inheritance has male-to-male transmission?
- autosomal dominant
Can X-linked recessive inheritance have male-to-male transmission?
NO
In X-linked recessive inheritance, what is the one situation where a carrier female will express some phenotype?
- when she has unbalanced X-inactivation
What type of pedigree is this?
X-linked recessive
- males exclusively affected*
- *unless unbalanced X-inactivation in heterozygous female
Four features of X-linked recessive inheritance:
- males exclusively affected*
- *unless unbalanced X-inactivation in females
- Gene transmitted from affected male to all daughters
- Mutant allele may be transmitted through a series of carrier females
Distinguishing features of X-linked dominant inheritance:
- trait never passed from father to son
- affected father and normal female parents will have:
- all affected daughters
- all normal sons
What type of pedigree is this?
X-linked dominant
- all daughters of affected male are affected
- all sons of affected male are normal
What types of genotype does phenotype occur in dominant inheritance?
- homozygote and heterozygote
- homozygotes more severely affected
What types of genotype does phenotype occur in recessive inheritance?
- homozygote, hemizygote, compound heterozygote
What type of inheritance pattern are males and females equally affected?
autosomal dominant and autosomal recessive
What type of inheritance pattern are males affected much more than females?
X-linked recessive
What type of inheritance pattern are females affected more than males?
X-linked dominant
Reduced penetrance definition:
- when the probability that a mutant gene will have a phenotypic expression is less than 100%
- “all or none” phenotype
Variable expressivity definition:
- when the severity of expression of the phenotype among individuals with the same disease-expressing genotype is different
Sex-limited traits definition:
- when autosomal mutations are inherited by both sexes, but the phenotype is only evident in one sex
- due to anatomical or physiological differences
Male-limited precious puberty is a form of what type of inheritance?
- autosomal dominant sex–limited phenotype
- only boys affected
Hemochromatosis is a form of what type of inheritance?
autosomal recessive sex-limited trait
- more common in males
- a disease caused by excess iron
- females rid excess iron through pregnancy and menstruation
Mosaicism definition:
- the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg.
- pure somatic
- pure germline
How to determine germline mosaicism:
- both parents normal and test negative for being carriers; more than one child affected with a highly penetrant AD or XL-R disorder
- all gametes of one parent are affected
Genetic lethal definition:
- diseases that are produced by dominant alleles with effects so severe that persons with them do not have children
Seven factors that create exceptions to Mendelian rules:
- Reduced penetrance
- Variable expressivity
- Sex-limited traits
- Germ-line mosaicism
- Genetic Imprintng
- New Mutations
- Misattributed Paternity
Genomic imprinting definition in regard to inheritance:
- when the sex of the transmitting parent plays a role in the expression of the phenotype in affected children
- “parent of origin” specific pattern is present in all somatic cells, but reversed in germ cells
Genetic imprinting (methylation) is reversed in:
the gametes
Two most common disorders which arise from genetic imprinting affecting pedigrees:
- prader-willi
- angelman syndrome
DELETIONS OCCUR ON SAME REGION OF CHROMOSOME 15
Prader-Willi syndrome:
- loss of paternally inherited gene
- 20 maternally imprinted genes affected
- excessive weight gain, motor and developmental delays
Angelman syndrome:
- loss of maternally inherited gene
- one paternally imprinted gene is affected
- severe mental retardation/happy/non-verbal
