Unit 2 Day 8 Flashcards

1
Q

genetic testing definition

A
  • analyzing an individual’s genetic material to determine predisposition to particular conditions or to confirm diagnosis
  • risk or diagnosis*
  • examine blood/fluid/tissue for markers (biochemical, chromosomal, genetic) that indicate presence/absence of disease
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2
Q

loose definition of genetic testing

A

tests informing risks/diagnosis of genetic disease

  • genetic tests are not solely restricted to DNA basis*
  • other tests can diagnose genetic conditions*
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3
Q

what is chromosomal analysis useful for?

A
  • identifying aneuploidies (trisomy 21)
  • identifying large chromosomal structural changes (duplication, deletion, rearrangements)
  • 3-5 mb
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4
Q

WAGR syndrome

A
  • high resolution chromosmal analysis
  • wilims tumor, aniridia, genitourinary malformation, retardation
  • on 11p13, must be 3-5 mb or larger
  • find w/ PAX6 locus in FISH
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5
Q

Fish analysis

A
  • specific, cost efficient if know/strongly suspect the diagnosis
  • micro-dup/del syndromes
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6
Q

what test do you use when you don’t know the diagnosis?

A

a “genomic” test

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7
Q

CMA-chromosomal microarray analysis

A
  • test and reference DNA sample targets
  • labeled w/ diff colors and washed across array covered in probes
  • abnormal ratios indicate deletions/duplications
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8
Q

microarray/aCGH

A
  • array comparative genomic hybridization
  • looks for deletions, shows them in same location
  • can compare sizes of similar deletions to see which zone is the critical disease region
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9
Q

dna sequencing

A
  • mutations in known genes, polymorphic variants, small (1-100nt) deletion/insertions
  • looks at sequence of known disease gene
  • DETECTS NOVEL MUTATIONS
  • may miss larger deletions
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10
Q

diagnostic testing

A
  • patient with signs/symptoms of disease

- positive genetic test result confirms diagnosis

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11
Q

predictive testing

A
  • patient with no signs/symptoms of genetic disease

- positive genetic provides estimate of future disease risk

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12
Q

allelic heterogeneity

A

different mutations (alleles) at a single locus

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13
Q

genetic heterogeneity

A

different mutations (alleles) at different loci

  • SC: 1 mutation, 1 gene
  • CF: many mutations, 1 gene
  • AD: many genes/mutations
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14
Q

informativity as a concept when genetic test is normal

A
  • some negative results are truly negative

- other negative results are non-informative (do not exclude diagnosis/risk)

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15
Q

OTC Deficiency

A
  • X linked disease
  • Urea cycle defect
  • designed for healthy OTC patients, Jessie Gelsinger enrolled for therapy
  • adenoviral vector + otc gene used
  • he died after large dose of intra-hepatic drugs (treatment may have tempered if they had looked at bloodwork)
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16
Q

chromosomal mutation challenges

A
  • cannot remove, silence, regulate extra chromosomal material
  • cannot insert missing material
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17
Q

single gene mutation challenges

A
  • cannot remove, silence, or regulate single genes

- cannot insert single genes

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18
Q

complex (genes+environment) mutation challenges

A
  • cannot remove, silence, or regulate multiple genes
  • cannot insert multiple genes
  • gene environment interactions not fully understood
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19
Q

genetic approach to human diseases

A
  • general management
  • primary disease specific therapies (if they exist)
  • genetic counseling
  • secondary prevention
  • primary prevention
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20
Q

therapies for metabolic disorders

A
  • usually due to enzyme deficiency
  • some can do dietary/pharmacological intervention
  • newborn screening, early diagnosis, treatment (less morbidity)
21
Q

treatment strategies for metabolic disorders

A
  • avoidance
  • dietary restriction (PKU)
  • replacement
  • diversion
  • inhibition
  • depletion
22
Q

protein replacement approaches

A
  • Alpha-1 AT: autosomal recessive, deficient, elastases unchecked, treat w/ recombinant AT1 therapy
  • Fabry: x linked, deficient in alpha-galactosidase a, treat with recombinant Alpha-gal
23
Q

Fabry treatments

A
  • glucose injections
  • chaperone based therapies
  • enzyme replacement therapy
  • chaperone + enzyme
24
Q

challenges to protein-based therapies?

A

production, delivery, targeting, imm. reactions, cost

25
gene therapy
- intro of dan into human cells to treat disease - should cure/slow progression of disease - done with non-viral (naked DNA and liposomes), adenoviral (dna viruses), and retroviral (rna viruses) - includes in vivo and ex vivo strategies
26
x linked disorders
- mutations on x chromosomes - mostly affects males - no male to male transmission
27
x linked recessive inheritance
- phenotype expressed in all males who carry affected genotype - phenotype in homozygous females only - heterozygote females=carriers
28
x linked dominant inheritance
-expressed male hemizygotes and female heterozygotes
29
x linked dominant diseases
``` Hypophosphatemic Rickets Alports Fragile X Syndrome Charcot Marie Tooth Incontinentia Pigmenti Rett Syndrome Orofaciodigital Syndrome Focal Dermal Hypoplasia ```
30
hypophosphatemic rickets
- 1/20000 - short stature - bone deformity - mutation in PHEX regulates fibroblast growth factor - kidneys unable to reabsorb phosphate
31
fragile X
-x linked, CGG repeats -1/2500-4000 males; 1/7-8000 females -most common cause inherited mental delay -maternal transmission bias -dysmorphic features, autistic, biting, aggression, etc. -FMR1, FMRP, Xq27.3 mutation -protein for normal cognitive development/female reproductive function 46-55 repeats is grey zone 56-200 is premutation >200 full mutation
32
rett syndrome
- x linked dominant - 1/10000 females - 95% new mutation rate - abnormal movement/coordination, loss communication, failure to thrive, seizures - MECP2 mutation - Methyl Cpg bp, impt nerve cells
33
x linked recessive disorders
``` Lesch-Nyhan Syndrome Dystrophinopathies Hunter’s Disease Menkes Disease Glucose 6 phosphate dehydrogenase deficiency Hemophilia A and B Wiscott Aldrich Syndrome Colorblindness ```
34
lesch-nyhan syndrome
- x linked recessive - 1/ 380000 - neurological/behavioral abnormalities - uric acid overproduction - HPRT1 mutation (recycles purines)
35
dystrophinopathies
- x linked recessive - spectrum muscle disease - Duchenne and Becker Muscular Dystrophy - DMD mutation, dystrophin - Xp21-21.1 (largest human gene)
36
duchenne musc. dystrophy
- progressive muscular weakness - calf weakness - ck levels=10x - dead in 30's, absence dystrophin
37
Becker muscular dystrophy
- progressive muscular weakness - ck levels=5x - later onset, dead 40's - abnormal quantity/quality dystrophin
38
hemophilia A
- recessive - 1/4000 - 10% female carriers affected - F8 mutation - Xq28 - 50% caused by 22A inversion
39
replicative segregation
- at cell division, multiple copies of tDNA replicate and sort randomly among newly synthesized mitochondria - normal or mutated DNA
40
Kearns-sayre
- mitochondrial inheritance - 1-3/100000 - somatic mutation - affects eyes, cardiac conduction, ataxia, deafness, kidney issues - deletion of mtDNA (removes 12 genes commonly)
41
MELAS
-Mitochondrial encephalomyopathy -1 in 300,000 -Low new mutation rate -muscle weakness, seizures, stroke-like episodes, lactic acidosis 80% caused by mutation in MT-TL1
42
MERRF
-mitochondrial -Myoclonic epilepsy with ragged-red fibers -1/400000 -low new mutation rate -muscle symptoms, seizures, ataxia, dementia mutations in MT-TK
43
leber hereditary optic neuropathy
- mitochondrial inheritance - 1/30-50000 europeans - vision loss - mutations in MT-ND genes
44
achondroplasia
- major features: prenatal, rhizomelic short stature, spinal cord compression, brainstem compression - 1/40000 - beteen 3-7% die unexpectedly in 1st year - due to advanced paternal age - autosomal dominant - FGFR3 Gly380Arg substitution-->gain of function - spinal cord compression (and apnea) most feared complication
45
nonsyndromic deafness
- congenital deafness is commonly recessive form - progressive childhood deafness is the dominant form often - 3/4 of genetic are non syndromic. GJB2 mutations are most common mutation.
46
syndromic deafness
- systems outside of ears involved | - different combinations can indicate different diseases/syndromes
47
GJB2 mutations
- recessive inheritance for severe congenital - parents=carriers - LOF mutations - autosomal dominant progressive with childhood onset * genetic, autosomal recessive, non syndromic deafness due to this mutation=most common category of congenital deafness*
48
FMR1 Gene
- fragile X syndrome - haplotype effect, full triplet expansion - premutation vs. mutation - full mutations have absent/reduced FMRP protein - premuations are not hypermethylated, have increased FMRP RNA - fragile X triplet repeat is in 5'UTR region