Genetics Flashcards
Codominance
Definition
Example
Bole alleles contribute to the phenotype of the heterozygote
Blood Group A, B, AB
Variable Expressivity
Definition
Example
Phenotype varies among individual with same genotype
Neurofibromatosis type 1
Incomplete Penetrance
Definition
Example
Not all individuals with the mutant genotype show the mutant phenotype
BRCA1 gene mutation do not always result in breast or ovarian cancer
Pleiotropy
Definition
Example
One gene contributes to multiple phenotypic effects
PKU
Imprinting
Definition
Physiology
Example
Differences in gene expression depend on whether the mutation is of maternal or paternal origin
At some loci, only 2 allele is active depending on which parent it came from
Prader Willi and Angelman’s Syndrome
Anticipation
Definition
Example
Increased severity or earlier onset of disease in succeeding generations
Huntington’s Disease
Loss of Heterozygosity
Definition
Example
Two Hits needed for disease, born with one mutation
Retinoblastoma and other tumor suppressors
Dominant Negative
Definition
Example
Heterozygote produces disease
Nonfunctional TFs binding prevents wild-type from binding
Linkage Disequilibrium
Definition
Where is it measured
Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance
Measured in a population, not in a family, and often varies in different populations
Mosaicism
Definition
Where can it occur
Example
Cells in the body differ in genetic make up due to post fertilization loss or change of genetic information during mitosis
Can be germ-line which produces disease not carried by either parent’s somatic cells
Bone marrow stem cells –> hematologic mosaic. Fused zygote
Locus Heterogeneity
Definition
Example
Mutations at different loci can produce the same phenotype
Marfan’s, MEN2B, and Homocystinuria can all cause marfanoid habitus. Albinism
Heteroplasmy
Examples
Presence of both normal and mutated mtDNA resulting in variable expression in mitochondrial inherited disease
Myclonic Epilepsy
Uniparental disomy
What is it?
How do you tell when the error happened?
Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other
Heterodisomy (heterozygous): Meiosis I error
Isodisomy (homozygous): Meiosis II error or post zygotic loss of 1 chromosome and duplication of the other
Hardy-Weinberg Population Genetics
Equation
Assumptions
In X linked recessive disease
(p^2) + 2pq + (q^2) = 1 and p+q=1
No mutations, Selection, Migrations and random mating
The frequency of an X linked recessive disease in males is q and in females is (q^2)
Prader-Willi Syndrome Chromosome Which allele is not expressed? What can cause it? Presentation
Inactivation or deletion on chromosome 15
Paternal allele is not expressed
Can also occur as a result of uniparental disomy
Mental retardation, hyperphagia, obesity, hypogonadism, hypotonia
Angelman's Syndrome Chromosome Which allele is not expressed? What can cause it? Presentation
Inactivation or deletion on chromosome 15
Maternal allele is not expressed
Can also occur as a result of uniparental disomy
Mental retardation, Seizures, Ataxia, Inappropriate laughter
Hypophosphatemic rickets
PathoPhys
Presentation
Genetics
↑ Phosphate wasting in PT of kidney
Rickets-like presentation
X linked Dominant
Mitochondrial myopathies Genetics PathoPhys Presentation Histo
Mitochondrial Inheritance
Mutations affecting Mito function
Myopathy and CNS disease (seizures)
Muscle biopsy shows ragged red fibers
Familial Hypercholesterolemia AKA PathoPhys Blood test Heterozygotes vs Homozygotes Presentation Risk of what?
Hyperlipidemia Type IIA Absent of defective LDL receptor Elevated LDL in blood Heterozygotes have cholesterol of 300 Homozygotes have cholesterol of 700 Severe atherosclerotic disease in early life. Tendon xanthoma (classically in the achilles tendon) MI may develop before age 20
Hereditary Hemorrhagic Telangiectasia AKA What organ system affected? How? Genetics Presentation
Osler-Weber-Rendu Syndrome
Disorder of blood vessels with arteriovenous malformations
Autosomal dominant
Telangiectasia, Recurrent Epistaxis, Skin discoloration
Hereditary Spherocytosis Inheritance What happens? Mutation Presentation Treatment
Autosomal dominant Spheroid erythrocytes Spectrin or Ankyrin defective Hemolytic anemia, ↑ mean corpuscular hemoglobin concentration (MCHC) Splenectomy is curative
Huntington's Disease Inheritance Presentation Gross PathoPhys Age of onset Genetics with chromosome and pathology
Autosomal dominant
Depression, Dementia, Choreiform movements
Caudate atrophy
↓ GABA and ACh in brain
20-50
Huntington gene on chromosome 4 with trinucleotide repeats (CAG) “Hunting 4 food”
Marfan Syndrome Inheritance Mutation Organs affected Presentation Risks associated with it?
Autosomal dominant
Fibrillin 1 gene mutation
Connective tissue of skeleton, heart, and eyes
Tall w/ long extremities, Hypermobile joints, long tapering fingers and toes (arachnodactyly)
Cystic Medial necrosis of the aorta –> aortic incompetence and dissecting aneurysm, Floppy Mitral Valve, Subluxation of the lenses
Neurofibromatosis Type 1 Name Inheritance Findings Chromosome
Von Recklinghausen’s Disease
Autosomal dominant
Cafe-au-lait spots, Neural tumors, Lisch nodules (pigmented iris hamartomas)
Long arm of chromosome 17
Neurofibromatosis Type 2
Inheritance
Presentation
Genetics with chromosome
Autosomal dominant
Bilateral acoustic schwannomas and Juvenile cataracts
NF2 gene on chromosome 22
“Type 2 = 22”
von Hippel-Lindau disease Inheritance Findings What are they at risk for? Genetics with chromosome PathoPhys
Autosomal dominant
Hemangioblastomas of retina/cerebellum/medulla
Multiple bilateral renal cell carcinoma and other tumors
Deletion of VHL gene (tumor suppressor) on chromosome 3p
Constitutive expression of HIF transcription factor and activation of angiogenic growth factor
Cystic Fibrosis Inheritance Genetics with chromosome PathoPhys with presentation What happens to the protein
Autosomal recessive
Defect in CFTR gene on chromosome 7
Defective Cl channel –> secretion of abnormally thick mucus that plugs lungs, pancreas, and liver –> recurrent pulmonary infections (Pseudomonas and S aureus), chronic bronchitis, Bronchiectasis, Pancreatic insufficiency (malabsorption and steatorrhea leading to VitKADE deficiency), Nasal polyps, Meconium ileus
Abnormal folding –> degradation before reaching cell surface
Normal function of CFTR
secretes Cl in lungs and GI tract and reabsorbs sweat
Cystic Fibrosis Male presentation Infant presentation Race affected Diagnostic test Treatment
Infertility in males due to bilateral absence of vas deferens
Failure to thrive in infants
Most common lethal genetic disease of whites
↑ concentration of Cl in sweat test
N-acetylcysteine to loosen mucous plugs (cleaves disulfide bonds within mucous glycoproteins)
X Linked Recessive Disorders
Names
Presentation in females
“Be Wise, Fool’s GOLD, Heeds Silly HOpe”
Bruton’s agammaglobulinemia, Wiskott-Aldrich syndrome, Fabry’s disease, G6PD deficiency, Ocular albinism, Lesch-Nyhan syndrome, Duchenne’s (and Becker’s) muscular dystrophy, Hunter’s Syndrome, Hemophilia A and B, Ornithine transcarbamoylase deficiency
Female carriers may be affected and may have less severe symptoms due to random X chromosome inactivation
Duchenne's Muscular Dystrophy Inheritance Mutation PathoPhys Presentation Time of onset Risk of what? Diagnosis
X linked recessive Frameshift mutation of dystrophin gene Accelerated muscle breakdown Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscle. Use of Gower's Maneuver requiring assistance of upper extremities to stand up Onset before 5 years of age Risk of Cardiac Myopathy ↑ CPK and muscle biopsy
Becker's Muscular Dystrophy Inheritance Mutation Severity Onset Diagnosis
X linked mutated dystrophin gene
Less severe
Adolescence or early adulthood
↑ CPK and muscle biopsy
Fragile X syndrome Inheritance Mutation PathoPhys Frequency Findings
X linked
Trinucleotide repeat disorder (CGG)
Defect affecting methylation and expression of FMR1 gene
2nd most common cause of mental retardation after Down syndrome
Macroorchidism (enlarged testes), Long face with Large jaw, Large everted ears, Autism, MVP
Longest human gene
Dystrophin gene
High rate of spontaneous mutation
Function of Dystrophin
Helps anchor muscle fibers, primarily in skeletal and cardiac muscle
Trinucleotide Repeat Expansion Diseases
Names
Repeat sequence
How does it change over generations
"Try Hunting for My Fried Eggs" "X-Girlfriend's First Aid Helped Ace My Test" Fragile X: CGG Friedreich's ataxia: GAA Huntington's: CAG Mytonic dystrophy: CTG Shows anticipation
Down Syndrome AKA Frequency Findings What are they at risk for?
Trisomy 21 (“Drinking Age is 21”)
Most common viable chromosomal disorder and most common cause of genetic mental retardation
Mental retardation, Flat Facies, Prominent Epicanthal Folds, Simian Crease, Gap between 1st 2 toes
Risk for Duodenal atresia, Congenital Heart Disease (ostium primum type ASD), ALL, and Alzheimer’s disease
Down Syndrome
Cause of trisomy?
Who is at risk?
Diagnosis
95% due to meiotic nondisjunction of homologous chromosomes (advanced maternal age)
4% due to Robertsonian translocation
1% due to Down Mosaicism (no maternal association)
↓ α fetoprotein, ↓ estriol, ↑ β-hCG, ↑ inhibin A, and US shows ↑ Nuchal in 1st trimester translucency
Edward's Syndrome AKA Findings What are they at risk for? Course Diagnosis
Trisomy 18 (“Election age is 18”)
Mental retardation, Rocker-Bottom Feet, Micrognathia (small jaw), Low-Set Ears, Clenched hands, Prominent Occiput
Risk of Congenital Heart Defects
Death within 1 year
↓ α fetoprotein, ↓ estriol, ↓ β-hCG, Normal inhibin A
Patau's Syndrome AKA Presentation What are they at risk for? Course Diagnosis
Trisomy 13 (“Puberty 13”)
Mental retardation, Rocker-bottom feet, Microphthalmia (small eyes), Microcephaly, Cleft lip, Clefp Palate, Holoprosencephaly (forebrain lacks 2 hemispheres), Polydactyly
Risk of Congenital Heart Disease
Death within 1 year
↓ PAPP-A, ↑ free β-hCG, ↑ nuchal translucency
Non disjunction in meiosis I
2 homologous chromosomes in 2 cells, Missing chromosome in 2 cells
Non disjunction in meiosis II
2 identical chromosomes in 1 cell, 2 normal cells, 1 cell missing a chromosome
Robertsonian Translocation
Mechanism
Chromosomes involved
Nonreciprocal translocation. Fusion of 2 acrocentric chromosomes and loss of short arms
13, 14, 15, 21, 22
Cri-du-chat Syndrome
What is it?
Presentation
Risk of what?
Congenital microdeletion of short arm of chromosome 5 Microcephaly, Mental Retardation, High pitched crying (mewing), Epicanthal folds Cardiac Abnormalities (VSD)
William’s Syndrome
What is it?
Presentation
Congenital microdeletion of long arm of chromosome 7 (including elastin gene)
Elfin facies, Intellectual disability, HyperCa (↑ sensitivity to VitD), well developed verbal skills, extreme friendliness with strangers, Cardiovascular problems
22q11 Deletion Syndrome
Presentation
Subtypes
What is it due to?
“CATCH 22”
Variable presentation: Cleft palate, Abnormal facies, Thymic aplasia (leads to T cell deficiency), Cardiac defects, HypoCa secondary to parathyroid aplasia
DiGeorge Syndrome: Thymic, Parathyroid, and Cardiac defects
Velocardiofacial Syndrome: Palate, Facial and Cardiac defects
Aberrant development of 3rd and 4th branchial pouches
