Patterns Of Single Gene Inheritance Flashcards
What are the exceptions to Mendelian patterns of inheritence?
Reduced penetrance
Variable Expressivity
Germ-line mosaicism
Genetic imprinting
New Mutations
Misattributed paternity
Mitochondrial gene disorders TNR disorders (just special features)
What is a compound heterozygote?
Both alleles are mutant, but mutations are at different locations on the gene
What is hemizygous?
Abnormal gene is located on X chromosome, in male pt
What is allelic heterogenity? Phenotypic heterogeneity?
Allelic: different mutations at same locus cause a similiar phenotype
Phenotypic: Disease appears different, but mutations are happening at same gene. Contributes to spectrum of a disorder
What is locus heterogeneity?
Phenotype being caused by more than one gene mutations.
I.e. Long QT syndrome (potassium, sodium, and structural proteins can cause it)
What is pleiotropy?
One gene that affects multiple traits
What are the factors that could confound pedigree interpretation?
- Early lethality of disorder
- Small family size
- Variable age of onset
- Non-mendelian inheritance
What are some features of Autosomal Recessive (AR) disease? What do these mutant alleles present as?
Must have 2 mutant alleles and no wt.
->type of mutation at each allele can be different (compound heterozygote)
Reduce or eliminate function of gene
Often affect function of enzymes
RARE
Unaffected child being carrier: 2/3
Either sex: 1/2 being carrier.
What are key features of AR?
Parents are unaffected, asymptomatic carriers
Males at same risk of females
Phenotype found in sublings (not parents or kids of affected
What factors can affects the risk of inheritance of an AR disorder?
- Carrier frequency in a given pop.
- Consanguinity
- Inbreeding
- Genetic isolated
What are features of AD pedigree?
1.Every affected individual has an affected parent
->no skipping generations
(also BB homozygotes are rare)
2. Male=females, & there is M2M transmission
- 1/2 offspring of an affected individual are affected
- Normal siblings of affected individuals have normal offspring.
- 2 affected parents (heterozygotes->75% offspring)
What is incomplete dominance in terms of AD pedigrees? What are examples?
An individual who is homozygous for the AD mutation will be more severely affected than heterozygotes
Achondroplasia
Familial Hypercholesterolemia
What is reduced penetrance? Variable expressivity?
Reduced penetrance: Probability a mutant gene will have any phenotypic expression at all
If that probability is less than 100 = reduced penetrance
I.e. AD form of Split-Hand Foot malformation
Variable expressivity:
Severity of the expression of the phenotype among indiv. With same disease-expressing genotype
Neurofibromatosis
Sex-linked autosomal traits include:
- Genes occur on autosomes and mutations present in both sexes
- Phenotype only evident in one sex
- Genes for the trait can be carried and transmitted by the opposite sex b/c anatomical or physiologic differences.
What is an example of an sex-linked AD disorder?
Male-limited precocious puberty
- > mutation in luteinizing hormone receptor gene
- > constitutive active LHR
- > phenotype expressed in males only
Heterozygous females dont have phenotype but male child can be affected.
Transmited by affected males/unaffected females
Sex-limited phenotype in AR disorders (examples):
- Hemochromatosis
- >most common single-gene inherited disease in the US
Males>Female (5-10X) w/p physiologic process to reduce excess iron.
In X-linked recessive disorders, what are expected outcomes between unaffected male and carrier female?
1/2 Risk of Females carrying
1/2 risk male will be affected
What is expected outcome of affected male and unaffected female in XLR?
All females are obligate carriers
All males are normal (no M2M transmission)
Skips geneation
When does X-linked inactivation come into play?
XLR. Somatic mosaics. Unbalanced X-inactivation
X-linked dominant patterns of inheritance?
No male to male transmission.
->Affected male and normal female =>
All daughters affected
All sons normal
What is mosaicism?
Presence in an individual of at least two cell lines that differ genetically but are derived from single zygote.
Somatic: present in some tissues in embyro, but not germ cells
-Pure germline mosaicism
What are clues in a pedigree that could unveil a germline mosaicism?
Parents that are phenotypically normal and who test negative for being a carrier AND have more than one child affected with a highly penetrant AD or XLR disorder
- > Osteogenesis imperfecta
- > Hemophilia A/B
- > Duchenne muscular dystrophy
What is the probability of a new mutation forming in a gamete?
10^-5/6 per gamete
RARE
Diseases produced by dominant alleles with affects so severe persons with them do not have children.
What is cause of Prader-Willi/Angelman syndrome?
Large deletions in gene, but gene that is present silenced thru epigenetics.
Prader-Will = 20 maternally imprinted genes affected
Angelman = 1 paternal gene
