Genetics Flashcards
Codominance example
Blood group, A,B,AB
Antitrypsin deficiency
HLA groups
Codominance
Both allele contribute to the phenotype of the hererozygote
Variable expressivity example
2 patients with NF1 may have varying disease severity
Variable expressivity
Phenotype varies among individuals with same genotype
Incomplete penetrance example
BRCA1 gene mutations do not always result in breast or ovarian cancer
Incomplete penetrance
Not all individuals with mutant genotype show the mutant phenotype
Pleiotropy
One gene contributes to multiple phenotypic effects
Pleiotropy example
Untreated phenylketonuria manifests with light skin, intellectual disability, musty body odor
Anticipation
Increased severity or earlier onset of disease in succeeding generations
Anticipation example
Trinucleotide repeat diseases (Huntington)
Loss of heterozygosity
If patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. Not true of oncogenes
Dominant negative mutation example
Mutation of a transcription factor in its allosteric site. Nonfunctioning mutant can still bind DNA, preventing wild-type transcription factor from binding
Loss of heterozygosity example
Retinoblastoma and the 2-hit hypothesis
Lynch syndrome
Li-fraumeni syndrome
Dominant negative mutation
Exerts a dominant effect. A heterozygote producse a nonfunctional altered protein that also prevents the normal gene product from functioning
Mosaicism
Presence of genetically distinct cell lines in the same individuals. Arises from mitotic errors after fertilization
Somatic mosaicism
Mutation propagates through multiple tissues or organs
Linkage disequilibrium
Tendency of certain alleles at 2 linked loci to occur together more often than expected. Measured in population, not in a family, often varies in different populations
Gonadal mosaicism
Mutation only in egg or sperm cells. If parentts and relatives do not have the disease, suspect gonadal or germline mosaicism.
Locus heterogeneity (and exampl)
Mutations at different loci can produce a similar phenotype
example: Albinism
Heteroplasmy
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease
Allelic heterogeneity
Different mutations in the same locus produce the same phenotype
example: β-thalassemia
Uniparental disomy (and types)
Offspring receive 2 copies of a chromosome from 1 parent and no copies from the other:
- Heterodisomy (heterozygous)
- Isodisomy (homozygous)
Hererodisomy (homozygous) pathophysiology
Meiosis 1 error
Uniparental is euploid or aneuploid
Euploid (correct number of chromosomes)
Isodisomy (homozygous) pathophysiology
Meiosis 2 error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair
Most common phenotype of uniparental disomy
Normal phenotype
Consider uniparental disomy in an individual:(when)
Recessive disorder when only one parent is a carrier
Hardy weinberg population
p and q are the frequencies of separate alleles
p^2+2pq+q^2=1……….p+q=1
q^2=frequency of homozygosity of q
p^2=frequency of homozygosity of p
2pq=frequency of heterozygosity (carrier frequency, if an autosomal recessive disease)
Frequency of X-linked recessive disease
Males:q
Females:q^2
Hardy-weinberg law assumptions include:
- No mutations occuring at locus
- Natural selection is not occuring
- Completely random mating
- No net migration
Impriting
At some loci, only one allele is active. The other is inactive (imprinted/inactivated by methylation
Imprinting/disease
With one allele inactivated, deletion of the active allele causes disease
Imprinting/disease examples
Both Parder-willi and Angelman syndromes are due to mutation or deletion of genes on ch15
Can also occur as a result of uniparental disomy
Prader-willi syndrome symptoms
- Hyperphagia
- Obesity
- Intellectual disability
- Hypotonia
- Hypogonadism
Prader-willy syndrome pathophysiology
Maternal imprinting and paternal gene deletion or mutation of chromosome 15
25% is due to maternal uniparental disomy (2 maternally imprinted genes)
Angelman syndrome symptoms
- Inappropriate laughter (happy puttt)
- Seizures
- Ataxia
- Severe intellectual disability
Angelman syndrome pathophysiology
associated with mutation or deletion of the UBE3A gene on the maternal copy of chromosome 15
5% paternal uniparental disomy
Autosomal dominant - characteristics
- Defects in structural genes
- Many generations
- Both male and female
- OFTEN PLEIOTROPIC (and variable expressive - different between individuals)
- Family history crucial for diagnosis
Autosomal recessive - characteristics
- 25% of offspring from 2 carrier parents are affected
- Enzyme deficiencies
- Usually only one generation
Often pleitropic. (Mode of inheritance)
Autosomal dominant
Which families have increased risk for autosomal recessive diseases
Consanguineous families
Autosomal recessive vs autosomal dominant (more severe?)
Autosomal recessive is commonly more severe. Patients often present in childhood
X linked most commonly affect males or females?
Males
X linked recessive
Sons of heterozygous mothers have 50% chance
No male to male
Females must be homozygous
skip generations
X linked dominant
- Transmitted through both parents
- Mother to son or daughter (50%)
- Father to daughters (100%)
- No father to son
- disease in every geenration
Hypophosphatemic rickets - definition / aka
X-dominant resulting in increased phosphate wasting at proximal tubule. Rickets-like presentation (Vit D resistant rickets)
Mitochondrial inheritance
Transmitted only through mothers to all offspring (variable expression due to heteroplasmy)
Mitochondrial myopathies pathophysiology
Secondary to failure in oxidative phosphorylation
X-dominant - example
- Hypophosphatemic rickets (Vit D resistant rickets)
- Rett syndrome
- Fragile X syndro,e
- Alport syndrome
Autosomal dominant type of genes
Structural genes
Mitochondrial myopathies symptoms (and examp)
Present with myopathy, lactic acidosis, CNS disease
ex. MELAS syndrome (mitrchondrial enchephalopathy, lactic acidosis, stroke-like episodes)
secondary to failure in oxidative phosphorylation
Autosomal recessive type of genes
Enzymes
Mitochondrial myopathies biopsy
Ragged red fibers due to accumulation of diseased mitochondria
Variable expression of mitochondrial inheritance disease is
Heteroplasmy
Mosaicism - example
McCune-Albright syndrome
McCune-Albright syndrome - due to
mutation affecting G-protein
McCune-Albright syndrome - presentation
- unilateral cafe-au-lait spots
- polyostotic fibrous dysplasia
- precosious puberty
- multiple endocrine abnormalities
- lethal if mutation before fertilization but survivable in patients with mosaicism
what is Leber hereditary optic neuropathy?
cel death in optic nerve neurons
clinical features in Leber neuropathy?
subacute bilateral vision loss in teens/young adults
90% males
usually permanent
