Genetics Flashcards
Pleiotropy
One gene contributes to multiple phenotypic effects.
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Loss of heterozygosity
If patient inherits or develops mutation in tumor suppressor gene, complementary allele must be deleted/mutated before cancer develops–not true of oncogenes.
Example: retinoblastoma, “two-hit hypothesis,” Lynch syndrome (HNPCC)
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Linkage disequilibrium
Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance.
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McCune-Albright Syndrome
RANDOM (NOT inherited) mutation that affects G-protein signaling, a phenomenon called mosaicism where some cells have mutation and some do not.
Presents with unilateral cafe-au-lait spots with ragged edges, polyostotic fibrous dysplasia (develop areas of abnormal scar-like (fibrous) tissue in their bones), and at least ONE endocrinopathy (eg precocious puberty).
Lethal if mutation before fertilization (affecting all cells), but survivable in parents with mosaicism.
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Locus vs. allelic heterogeneity
Locus heterogeneity: mutations at different loci produce similar phenotype (eg albinism)
Allelic heterogeneity: different mutations at same loci produce same phenotype (eg beta-thalassemia)
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Uniparental disomy
Offspring receives 2 copies of chromosome from 1 parent and non from the other–EUPLOID and NOT aneuploid.
HeterodIsomy = meiosis I error IsodIsomy = meiosis II error
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Imprinting
Examples of conditions due to imprinting errors?
Imprinting: at some loci, only one allele active and other inactive (eg by methylation, deletion, uniparental disomy)
Prader-Willi syndrome: maternal imprinting with paternal gene deleted/mutation –> P/W hyperphagia, obesity, ID, hypogonadism, hypotonia
Angelman Syndrome: paternal imprinting with maternal gene deleted/mutation –> P/W inappropriate laughter (“happy puppet”), seizures, ataxia, SEVERE ID
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Hypophosphatemic rickets (aka Vitamin D-resistant rickets)
X-linked dominant disorder resulting in increased phosphate wasting at proximal renal tubule.
P/W ricket symptoms: include delayed growth, bow legs, weakness, and pain in the spine, pelvis, and legs.
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Clinical findings for MELAS?
MELAS = mitochondrial encephalopathy, lactic acidosis, stroke-like episodes
Variable expression due heteroplasmy.
Secondary to failure in oxidative phosphorylation.
Muscle bx shows “ragged red fibers” due to accumulation of diseased mitochondria.
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Cystic Fibrosis
Genetics Pathophysiology Diagnosis Complications Treatment
Genetics - AR defect in CFTR gene (codes for ATP-gated Cl- channel that secretes Cl- in lungs and GI tract) on chromosome 7, commonly deltaf508 –> most common lethal genetic disease in Caucasians
Pathophysiology: Most common mutation results in misfolded protein that prevents proper protein trafficking –> results in decrease Cl- secretion.
Diagnosis: Cl- sweat test with pilocarpine. Can p/w contraction alkalosis and hypokalemia (ECF effects analogous to loop diuretic). Newborn screening can see increased immunoreactive trypsinogen.
Complications:
1) Recurrent pulmonary infections (esp. pseudomonas, s. aureus), hyperinflated lungs, chronic bronchitis/bronchiectasis –> reticulonodular CXR
2) Pancreatic insufficiency: fat malabsorption –> vitamin ADEK deficiencies, steatorrhea, diabetes
3) Hepatic insufficiency: biliary cirrhosis, liver disease
4) Infertility in men due to ABSENCE OF VAS DEFERENS, NOT due to inability to produce sperm
Treatment: aerosolized dornase alfa (DNAse), hypertonic saline, chest physiotherapy, pancreatic enzymes for insufficiency
Ivacaftor is medication specific for those with G551D mutation by increasing Cl- flux. Mutation does not have to do with impaired CFTR trafficking–protein is trafficked to protein surface but medication helps keep ion channel open.
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Down Syndrome
Genetic causes of trisomy 21?
Findings?
Associated conditions?
What would you find with fetus during first and second trimesters?
Genetic causes: most commonly (95%) due to meiotic nondisjunciton, but also unbalanced Robertsonian translocation (chromosomes 14 and 21) and least commonly due to mosaicism
Findings: ID, flat facies, prominent epicanthal folds, single palmar crease, Brushfield spots
Associated conditions: duodenal atresia, Hirschsprung disease, congenital heart defects (eg atrioventricular septal defect), increased risk of ALL and AML, associated with early onset Alzheimer’s
First Semester: US shows nuchal translucency and hypoplastic nasal bone; decreased serum PAPP-A, increased free beta-HCG
Second Semester: decreased alpha-fetoprotein, increased beta-hCG, decreased estriol, increased inhibin A
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Edwards Syndrome - findings?
Trisomy 18
PRINCE
Prominent occiput and micrognathia (small jaw) Rocker-bottom feet Intellectual disability Nondisjunction Clenched fists (overlapping fingers) Ears (low-set)
Death usually by age 1
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What are the chromosomes affected by Robertsonian translocation?
13, 14, 15, 21, 22
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Cri-du-Chat
Microdeletion of short arm of chromosome 5
High pitched cry, moderate to severe ID, microcephaly, VSD
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Williams Syndrome
Microdeletion of long arm of chromosome 7
Distinctive "elfin" facies ID Hypercalcemia due to increased sensitivity to vitamin D Well-developed verbal skills Friendliness with strangers
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