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Flashcards in Genetics Deck (59)
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Codominance

Both allele contribute to the phenotype of the hererozygote

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Codominance example

Blood group, A,B,AB
Antitrypsin deficiency
HLA groups

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Variable expressivity example

2 patients with NF1 may have varying disease severity

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Variable expressivity

Phenotype varies among individuals with same genotype

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Incomplete penetrance example

BRCA1 gene mutations do not always result in breast or ovarian cancer

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Incomplete penetrance

Not all individuals with mutant genotype show the mutant phenotype

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Pleiotropy

One gene contributes to multiple phenotypic effects

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Pleiotropy example

Untreated phenylketonuria manifests with light skin, intellectual disability, musty body odor

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Anticipation

Increased severity or earlier onset of disease in succeeding generations

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Anticipation example

Trinucleotide repeat diseases (Huntington)

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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

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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

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Loss of heterozygosity example

Retinoblastoma and the 2-hit hypothesis
Lynch syndrome
Li-fraumeni syndrome

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Dominant negative mutation

Exerts a dominant effect. A heterozygote producse a nonfunctional altered protein that also prevents the normal gene product from functioning

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Mosaicism

Presence of genetically distinct cell lines in the same individuals. Arises from mitotic errors after fertilization

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Somatic mosaicism

Mutation propagates through multiple tissues or organs

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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

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Gonadal mosaicism

Mutation only in egg or sperm cells. If parentts and relatives do not have the disease, suspect gonadal or germline mosaicism.

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Locus heterogeneity (and exampl)

Mutations at different loci can produce a similar phenotype
example: Albinism

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Heteroplasmy

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease

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Allelic heterogeneity

Different mutations in the same locus produce the same phenotype
example: β-thalassemia

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Uniparental disomy (and types)

Offspring receive 2 copies of a chromosome from 1 parent and no copies from the other:
1. Heterodisomy (heterozygous)
2. Isodisomy (homozygous)

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Hererodisomy (homozygous) pathophysiology

Meiosis 1 error

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Uniparental is euploid or aneuploid

Euploid (correct number of chromosomes)

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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

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Most common phenotype of uniparental disomy

Normal phenotype

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Consider uniparental disomy in an individual:(when)

Recessive disorder when only one parent is a carrier

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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)

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Frequency of X-linked recessive disease

Males:q
Females:q^2

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Hardy-weinberg law assumptions include:

1. No mutations occuring at locus
2. Natural selection is not occuring
3. Completely random mating
4. No net migration

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Impriting

At some loci, only one allele is active. The other is inactive (imprinted/inactivated by methylation

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Imprinting/disease

With one allele inactivated, deletion of the active allele causes disease

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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

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Prader-willi syndrome symptoms

1. Hyperphagia
2. Obesity
3. Intellectual disability
4. Hypotonia
5. Hypogonadism

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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)

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Angelman syndrome symptoms

1. Inappropriate laughter (happy puttt)
2. Seizures
3. Ataxia
4. Severe intellectual disability

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Angelman syndrome pathophysiology

associated with mutation or deletion of the UBE3A gene on the maternal copy of chromosome 15
5% paternal uniparental disomy

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Autosomal dominant - characteristics

1. Defects in structural genes
2. Many generations
3. Both male and female
4. OFTEN PLEIOTROPIC (and variable expressive - different between individuals)
5. Family history crucial for diagnosis

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Autosomal recessive - characteristics

1. 25% of offspring from 2 carrier parents are affected
2. Enzyme deficiencies
3. Usually only one generation

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Often pleitropic. (Mode of inheritance)

Autosomal dominant

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Which families have increased risk for autosomal recessive diseases

Consanguineous families

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Autosomal recessive vs autosomal dominant (more severe?)

Autosomal recessive is commonly more severe. Patients often present in childhood

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X linked most commonly affect males or females?

Males

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X linked recessive

Sons of heterozygous mothers have 50% chance
No male to male
Females must be homozygous
skip generations

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X linked dominant

1. Transmitted through both parents
2. Mother to son or daughter (50%)
3. Father to daughters (100%)
4. No father to son
5.disease in every geenration

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Hypophosphatemic rickets - definition / aka

X-dominant resulting in increased phosphate wasting at proximal tubule. Rickets-like presentation (Vit D resistant rickets)

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Mitochondrial inheritance

Transmitted only through mothers to all offspring (variable expression due to heteroplasmy)

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Mitochondrial myopathies pathophysiology

Secondary to failure in oxidative phosphorylation

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X-dominant - example

1. Hypophosphatemic rickets (Vit D resistant rickets)
2. Rett syndrome
3. Fragile X syndro,e
4. Alport syndrome

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Autosomal dominant type of genes

Structural genes

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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

51

Autosomal recessive type of genes

Enzymes

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Mitochondrial myopathies biopsy

Ragged red fibers due to accumulation of diseased mitochondria

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Variable expression of mitochondrial inheritance disease is

Heteroplasmy

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Mosaicism - example

McCune-Albright syndrome

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McCune-Albright syndrome - due to

mutation affecting G-protein

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McCune-Albright syndrome - presentation

1. unilateral cafe-au-lait spots
2. polyostotic fibrous dysplasia
3. precosious puberty
4. multiple endocrine abnormalities
5. lethal if mutation before fertilization but survivable in patients with mosaicism

58

what is Leber hereditary optic neuropathy?

cel death in optic nerve neurons

59

clinical features in Leber neuropathy?

subacute bilateral vision loss in teens/young adults
90% males
usually permanent