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140 Cards in this Set
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indications for prenatal diagnosis?
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mom >35 yo, abnormal AFP-4 quad screen, abnormal US, family history, teratogen exposure
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when can CVS be performed?
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10-12 wks
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advantages of CVS?
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results at 11-13 wks (amino at 17-22 wks)
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disadvantages of CVS?
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.5-1% chance of pregnancy loss; finger malformation or hyperplasia possible if <10 wks; cramping, false(+) mosaicism; maternal cell contamination; Rhogam prophylaxis
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what can be diagnosed with CVS?
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karotype of villie; single gene/Mendelian disorders; DNA or tissue enzyme analysis
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CVS cannot test for?
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neural tube defects and anatomic birth defect (eg congenital heart disease)
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when is amniocentesis performed?
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15-20 wks
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when do you need results for prenatal diagnosis to affect pregnancy management?
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22 wks
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what can you determine with amniocentesis?
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karyotype; FISH; AFP (spina bifida, abdominal wall defects, etc); acetyl cholinesterase (neural tube defects); single gene disorders
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followup for CVS?
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MSAFP (15 wks) and US (18 wks)
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what does first trimester US look for?
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congenital disorders (nuchal translucency, absence of nasal bones, etc)
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what does nuchal translucency indicate?
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ddx including tri21, congenital heart disease
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what does absence of nasal bones indicate?
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tri21 (60% of affected fetuses show)
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what is pre-implantation genetic diagnosis?
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uses in vitro fertilization for at risk couples; remove 1 blastomere --> PCR DNA analysis for known mutation
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what are maternal indications for fetal MRI?
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abdominal pain; hydronephrosis and urinary tract evaluation; adnexal masses; MRI pelvimetry; placental evaluation
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what are fetal indications for fetal MRI?
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CNS anomalies (corpus callosum agenesis, mega-cisterna magna); liver position with diaphragmatic hernia; fetal abdominal , lung and pelvic masses
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when does the neural tube close?
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28 days
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what are the goals of newborn screening?
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quick identification of newborns with rare, serious, but treatable disorder; early diagnosis and treatment of affected infants resulting in normal growth and development; reduction of significant human and financial costs for family and society
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what are features of a child born to a mother with uncontrolled PKU?
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microcephaly, mental retardation, congenital heart disease, pre/postnatal growth retardation, dysmorphic features (round face, short palpebral fissures, broad flat nasal bridge), hypertonicity, hyperactivity
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what are features of a child with untreated PKU?
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normal at birth, developed mental retardation, hyperactivity, irritability, spasticity, blonde hair, blue eyes, eczema, abnormal mousy odor
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why are children born to women with uncontrolled PKU abnormal?
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phenylalanine is a teratogen
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what are features of MCAD deficiency?
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hypoketotic hypoglycemia and hepatic failure; necessary to avoid fasting and MCFA; L-carnitine supplementation and formula; proper tx = normal growth and development
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what are features of galactosemia?
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inability to break down galactose leading to cataracts, mental retardation, hyperbilirubinemia, jaundice, cirrhosis, liver failure, premature ovarian failure, failure to thrive, vomiting, diarrhea, e. coli sepsis, death
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what is treatment for galactosemia?
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exclusion of galactose from diet
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what are features of biotinodase deficiency?
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unable to recycle biotin for carboxylase enzymes leading to rash, alopecia, seizures, hearing loss, vision impairment, neurological impairment, death
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screening test for congenital hypothyroidism?
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enzyme immuno assay: TSH and T4
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what is the procedure for questionable results for screens for congenital hypothyroidism?
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abormal = refer; repeat is borderline --> if still inconclusive = refer
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screening test for CAH?
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based on 17-OH progesterone and birthweight
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screening test for cystic fibrosis?
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pancreatic enzyme immunoreactive trypsinogen (IRT); top 4% of dailyr IRTs will have mutational analysis
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what is eugenics?
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improve inborn quality of human race, particularly through the control of hereditary factors
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what was done as part of the eugenics movement?
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involuntary sterilization of individuals with mental retardation, psychiatric disorders, seizures, and those convicted of a crime
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what are principles and goals of genetic counseling?
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respect for autonomy, privacy of the individual, need for informed consent, confidentiality, sensitivity to tendency toward directiveness and paternalism
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what are principles and goals of non-directive genetic counseling?
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information presented fairly and even-handedly, not with purpose of encouraging a particular course of action, devoid of eugenic motivation; may suggest different scenarios to help family think through their decision
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what are components of the genetic counseling interaction?
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information gathering (family and medical hx; expectations from consultation), establish or verify a diagnosis, risk assessment, information giving, psychological counseling
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what are the components of the genetic counseling communication process?
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help comprehend medical facts (diagnosis, probable course and management); appreciate hereditary contribution and recurrence risk; understand alternatives for dealing with recurrence risk; choose course of action in view of risk and family goals and beliefs; make best possible adjustment to disorder in an affected family member and/or recurrence risk
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what are more neutral terms for risk?
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chance or likelihood; avoid often, rarely, never, high, low
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alternatives for dealing with risk?
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take your chances; egg or sperm donor; preimplantation diagnosis; adoption; elect not to have children
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what is the process of preimplantation diagnosis and how is it performed?
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in vitro fertilization and genetic testing on the fertilized eggs in order to implant embryos that do not have the genetic abnormality; amniocentesis is used as confirmatory measure
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why is cystic fibrosis carrier screening being performed?
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90% of carriers can be detected and only 1/5 of new CF cases have a positive family history
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what does the current CF carrier screening test for?
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23 mutations (each occuring at least .1% frequency of all CFTR mutations in panethnic panel)
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how many and which conditions are included in the ashkenazi jewish carrier panel?
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11: CF, tay sachs, canavan disease, familial dysautonomia, bloom syndrome, fanconi anemia group C, gaucher, glycogen storage disease type 1a, MSUD, mucolipidosis type IV, Niemann-Pck type A
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what are the 5 most common diseases tested for in the ashkenazi jewish carrier panel?
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gaucher, cf, tay sachs, familial dysautonomia, canavan disease
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what is the first trimester maternal serum screening?
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2 analytes for screening for Down syndrome: PAPP-A is decreased in down syndrome and beta-hCG is increased in down syndrome
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what is the second trimester maternal serum screening?
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AFP, hCG, uE3, inhibin-A
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what results are expected in the second trimester maternal serum screening for a fetus with down sydnrome?
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AFP decreased
hCG increased uE3 decreased inhibin-A increased |
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what results are expected in the second trimester maternal serum screening for a fetus with tri18?
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AFP decreased
hCG decreased uE3 normal |
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what results are expected in the second trimester maternal serum screening for a fetus with NTD?
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AFP increased
hCG normal uE3 normal |
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what is looked for with the first trimester ultrasound screening?
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nuchal translucency and presence of nasal bones
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what does the finding of increased nuchal translucency suggest?
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down syndrome, tri18, tri13, turner syndrome, triploidy, congenital heart defects
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what does the absence of nasal bones on US suggest?
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down syndrome
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what is the use of first trimester maternal serum and ultrasound screening?
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detects 83% of down syndrome and 80% of tri18 cases between 10-13 weeks
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what relationship is there between a positive result for first trimester screening and affected fetus with downs?
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1/25 of women with positive result will have affected fetus
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what are the different types of FISH probes?
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centromeric, chromosome specific unique sequence (or locus specific), whole chromosome paint, subtelomeric
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what is the clinical application of centromeric probes?
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making rapid diagnosis of aneuploidy syndromes using non-dividing cells in interphase obtained from a prenatal sample
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what is the clinical application of chromosome specific unique sequence probes (locus specific probes)?
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detection of microdeletion syndromes (prader-willi/angelman, digeorge, williams); are complimentary to DNA sequences in a specific gene
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what is the clinical application of whole chromosome paint probes?
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characterizing complex chromosomal rearrangements and for identify origin of marker chromosomes; library that covers entire chromosome
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what is the clinical application of subtelomeric probes?
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stains tips and ends of chromosomes to identify subtelomeric deletions (rearrangements) that are otherwise difficult to visualize
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what are the clinical features and chromosomal gene locus for prader-willi?
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infantile hypotonia, childhood obesity, short stature, small hands/feet, hypogonadism, mental retardation, failure to thrive; paternal (del)15q11-13 aka maternal disomy 15
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what are the clinical features and chromosomal gene locus for angelman?
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happy puppet, severe mental retardation, hypotonia, ataxic gait, paraoxysmal laughter, absent speech, mandibular prognathism (protruding jaw); maternal (del)15q11-13 aka paternal disomy 15
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what are the clinical features and chromosomal gene locus for digeorge?
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tetralogy of fallot, thymus aplasia/hypoplasia, hypocalcemia, palatal abnormalities, velopharyngeal insufficiency, short stature, learning and behavior problems, large nose; (del)22q11.2
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what are the clinical features and chromosomal gene locus for williams syndrome?
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supravalvular aortic stenosis, short stature, variable mental retardation, overly friendly personality, stellate appearance of the iris, round face, full cheeks and puffy lips, short upturned nose, peri-orbiral fullness, hypercalcemia, global developmental delay; (del)7q11.23
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what is the methodology of array CGH (array comparative genomic hybridization)?
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looking for copy number variants, checking for any sequence that is present in a greater or smaller number of copies per genome in the test DNA compared to a normal control DNA; capable of detecting variants too small to be seen under microscope
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what is detectable by array CGH?
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unbalanced chromosomal rearrangement, abnormal copy numbers, chromosome abnormalities in children with normal karyotyes (detection of losses or duplications of chromosome regions)
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what is indicated test for a child with unexplained GDD, MR, or MCA?
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aCGH
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what are restriction fragment length polymorphisms?
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polymorphisms revealed by variation in lengths of restriction fragments
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how does a polymorphism generally manifest with RFLP?
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as the longer segment that do not migrate as far on the gel
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what does RFLP recognize?
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polymorphisms and possible association with a disease gene
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what are variable number tandem repeats?
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number of minisatellites in a given region
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what does VNTR indicate?
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reveal polymorphisms due to different numbers of repeats located between 2 restriction sites
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how do RFLPs and VNTRs differ?
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RFLPs reveal polymorphism becasue of presence/absence of restriction site where VNTR reveals polymorphisms due to different numbers of repeats located between two restriction sites
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what are short tandem repeats?
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microsatellites occuring in tandem up to several hundred and the number varies among individuals and even homologous chromosomes
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STRPs vs VNTRs?
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STRP differ in size and that they are not bounded by restriction sites; more abundant and evenly distributed --> polymorphism of choice in gene mapping
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allele specific oligonucleotides are used for?
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sensitive to single base pair mismatch between a probe and the sample so can test for the absence of the normal gene or the presence of a known mutation
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what disease can ASO be used for and what mutations does it detect?
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CF: detect normal sequence, delta F508, and G551D mutations
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what components are necessary for PCR?
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2 oligonucleotide primers, thermally stable DNA polymerase, large number of free DNA nucleotides, genomic DNA from an individual
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what are advantages of PCR?
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need only small amounts of DNA, rapid, large amounts of pure DNA so less often necessary to use radioactive probes to detect specific DNA sequences
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what are disadvantages of PCR?
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need flanking DNA sequence to make primer, susceptible to contamination, cannot be used to detect larger deletions and southern blotting is used instead
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what is a silent mutation?
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new codon encodes same aa
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what is a missense mutation?
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different aa encoded, possibly changing protein function
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what is a nonsense mutation?
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produces one of 3 stop codons
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what is a promoter mutation?
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mutation in promoter region that may decrease affinity of RNa polymerase for promoter site --> decreased gene expression
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what is a splice site mutation?
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mutation occuring at intron-exon boundries, altering splicing signal resulting in altered transcription
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when is the most critical period for teratogens when most structural anomalies are produced?
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2-8 wks post conception
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what are problems caused by teratogens after the most critical period and what is the time period?
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after 8-9 weeks will see problems of cell depletion leading to growth retardation
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what effects are seen on the fetus with teratogen exposure earlier than 2 wks?
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all or none
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what factors does teratogenicity depend on?
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nature of the agent, dose, route, gestational timing, presence of concurrent exposures, biological susceptibility of the mother and embryo/fetus
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what routes of exposure carry most risk to the fetus?
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systemic absorptions, radiation; others may not reach embryo until extensive metabolism by mother has occurred
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what are the teratogenic effects on the fetus from diabetes?
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neural tube defects (spina bifida); heart defects (cardiomyopathy); sacral agenesis; caudal regression (femoral dysplasia); fetal macrosomia (big baby); increased risk of fetal loss, abnormal fetal growth, neonatal hypoglycemia, polyhadramnios
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what are the teratogenic effects on the fetus from maternal PKU?
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microcephaly, mental retardation, prenatal growth deficiency, congenital heart disease, minor facial anomalies, diet for life
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what are the teratogenic effects on the fetus from cytomegalovirus?
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IUGR (intrauterine growth retardation); microcephaly with encephalitis resulting in periventricular calcifications, mental retardation, spasticity, hypotonia, seizures; jaundice; severe mental retardation; severe vision and hearing loss - sensorineural hearing loss
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what are the teratogenic effects on the fetus from phenytoin/dilantin?
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genetic metabolic defect causing peroxide hydrolase deficiency leading to vik K clotting factor depletion and decreases folate absorption; fetal hydantoin syndrome (2-11% risk); IUGR; mental retardation; cranio-facial abnormalities (microcephaly, short nose, low nasal bridge, midfacial hypoplasia, low-set or abnormal ears, wide mouth with prominent lips); nail and digital hypoplasia; congenital heart defects
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what are the teratogenic effects on the fetus from valproic acid?
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increased risk for NTD (spina bifida > anencephaly); IUGR; craniofacial defects; cardiac defects; skeletal and limb defects; congnitive delays and reported autism spectrum disorders
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what are the teratogenic effects on the fetus from accutane?
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ocular abnormalities; craniofacial abnormalities (eye and ear defects especially microtia, cleft palate, microcephaly); CNS - hydrocephalus; cardiac defects
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what are the teratogenic effects on the fetus from alcohol?
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facial abnormalities (short palpebral fissures, flat midface, low nasal bridge, short nose, long smooth philtrum, thin border of upper lip); prenatal onset growth deficiency; microcephaly; cognitive deficits; occasional major organ defects; gross and fine motor defects; ADHD, externalizing behaviors
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what are the teratogenic effects on the fetus from ionizing radiation?
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growth retardation; CNS - microcephaly; ocular defects when fetal loss has not occurred --> due to cell death and teratogenic effects, carcinogenesis, genetic effects and mutations
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what are the teratogenic effects on the fetus from tetracycline?
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bone and tooth staining
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what is the route of exposure and threshold for diabetes?
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transplacental; lower risk when mother HbA1C <8.5
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what is the route of exposure and threshold for maternal PKU?
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transplacental; Phe levels >10 mg/dL
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what is the route of exposure and threshold for CMV?
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from primary maternal infection; .2-2% of all newborns are infected but only 10% have serious problems at birth
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what is the route of exposure and threshold for phenytoin/dilantin?
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anticonvulsant drug; 2-3x risk for abnormalities
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what is the route of exposure and threshold for valproic acid?
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anticonvulsant
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what is the route of exposure and threshold for accutane?
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highly teratogenic; highest risk with oral use between 2-5 wks; topical preparation no absorbed greatly thus not considered teratogenic
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what is the route of exposure and threshold for alcohol?
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spectrum: no adverse effects to fetal loss, FAS; dependent on amount consumed, timing/duration of exposure; presence of other damaging agents, individual susceptibility
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what is the route of exposure and threshold for ionizing radiation?
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therapeutic vs diagnostic radiation exposure; >5 rads places fetus at risk; slower dosage rates reduces the effects of the total dose
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what is the route of exposure and threshold for tetracycline?
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use after 20 wks results in bone and tooth staining
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what is the inheritance and molecular defect of duchenne muscular dystrophy?
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x-linked recessive; dystrophin gene (Xp21) usually deleted resulting in absent dystrophin production (if not mutation found, must do a muscle biopsy
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what are clinical findings of dmd?
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progressive muscle weakness, nonambulatory by 12 yo; pseudohypertrophy of calves; gower sign (walking hands up legs); markedly elevated serum CK; 10-15% of sporadic cases due to germline mosaicism; tx = steroids and supportive care
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what is the inheritance and molecular defect of spinal muscular atrophy (werdnig-hoffman syndrome) aka anterior horn cell disease?
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AR; loss of function of SMNt (survival motor neuron) gene at 5q21 typically a homozygous deletions
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what are clinical findings of anterior horn cell disease?
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absent DTRs; weakness; fasciculations; normal facial grimace; lack of chest wall growth leading to diaphragmatic breathing; hypotonia and areflexic but alert - onset 0-6 months and respiratory death before 24 months
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what is the inheritance and molecular defect of neurofibromatosis I?
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AD with complete penetrance and variable expressivity; NF1 on chromosome 17, neurofibromin (GTPase activating protein)
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what is the diagnostic criteria of neurofibromatosis I?
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need 2 or more: 6 cafe au lait spots; skin fold freckles (axillary, inguinal) appear at 3-5 yrs; at least 2 cutaneous neurofibromas or one plexiform neurofibroma appearing at puberty; more than 2 lisch nodules (iris hamartomas); optic gliomas, onset in early childhoo; skeletal dysplasia (loss of tibia or orbit, hypoplasia of bone can result in fracture/pseudoarthritis); affected 1st degree relative
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what are other clinical features of neurofibromatosis I?
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increased risk for learning disabilities, ADHD, speech problems, hypotonia, 5-10% risk for malignant neurofibrosarcoma, 1/3 develop severe complication over lifetime including HTN, seizures, scoliosis
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what is the inheritance and molecular defect of tuberous sclerosis complex?
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AD; two genes: TSC1 at 9q34 is hamartin and TSC2 at 16p13 is tuberin; same phenotype as both act as tumor suppressors
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TSC is one of the most common conditions associated with what?
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autism
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what is tuberous sclerosis complex?
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multisystem genetic disorder involving the skin, heart, eyes, brain, and kidneys; presenting features vary but often with seizures and hypopigmented skin macules in infancy
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what clinical features are common with TSC?
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infantile spasms are typically first sign; hypomelanotic macules; subependymal nodules; cardiac rhabdomyomas (occur congenitally and usually regresss)
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what is the inheritance and molecular defect of fragile x?
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x-linked dominant; trinucleotide repeated expansion (CGG), hypermethylation of FMR1 gene turns off gene expression resulting in fragile x
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what clinical features are seen with fragile x syndrome?
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mental retardation; elongated face with prominent chin and ears, soft skin, hypotonia, macroorchidism in males (8-10 yrs); hypermobile joints, autism
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what is the inheritance and molecular defect of huntington's disease?
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AD; trinucleotide repeats (CAG) at 4p16.3 with gene product huntington
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how many repeats are considered mutation in fragile x?
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>200
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how many repeats are considered mutation in huntingtons?
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>39-121
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what are clinical features of huntingtons?
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depression, mood swings, dementia, chorea, brachykinesia, early onset associated with rigidity and is paternally derived; onset in 3rd - 4th decade with survival 15-20 yrs from onset of symptoms
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what conditions are autism associated?
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fragile x, TSC, untreated PKU, down; minor = duplication 15q, congential rubella syndrome
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what is the goal of expression profiling?
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determine best treatment course for an individual; expression pattern of a set of genes may provide information about the best treatment paradigm
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what is a microarray and how is it used?
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used to study gene expression testing expression of many genes at once against a 'normal'; samples are reverse transcribed and mixed and hybridized to slides with probes - fluorescence intensity determines level of gene expression
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what is the significance of gene variation?
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variations are likely to have different risks leading to concept of relative risk; even two people with same variant of one gene may have different age of onset, severity, etc because other genes may interact to modify the main gene
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what are SNPs?
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single nucleotide polymorphisms
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what is the clinical application of SNPs?
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may have no functional effect or cause disease, may increase risk for disease or drug sensitivities, used to assign risk for each allele in the population, combine all risk alleles to get overall risk estimate
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what are the advantages of genotyping?
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treatment and diagnosis of highly penetrant disease, transplant pts, identifying drug sensitivities, determining cancer prognosis and treatment reginmens, potential for impacting non-familial dz (diabetes, stroke, alzheimers)
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what are cons of genotyping?
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old school techniques are just as effective, few reliable gene markers for cancers and diseases, insurance for people with positive markers, inability for patients/doctors to understand risks
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what does diagnosis and prognosis rely on?
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expression profiling
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what does predictive testing rely on?
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SNP profiling
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what are the benefits of pharmacogenetics?
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increasing drug efficacy and eliminating safety concerns
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what is the goal of pharmacogenetics?
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linking differences in gene structure to drug metabolism and response
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what are applications of pharmacogenetics?
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individualizing drug therapy selection; predicting adverse reactions, dosing, response; identifying potential addiction; development of medications
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what does the cytochrome p450 system do?
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drug metabolizing enzymes that take non-water soluble molecules and make them water soluble to be eliminated in the urine
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inactivation or activation of therapeutic agents; conversion of chemicals to highly reactive molecules; participation in steps of steroid hormone synthesis; metabolism of fatty acids and derivatives
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why does differences in cytochrome p450 result in different drug tolerance/metabolism?
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restricted substrate specificity (1 enzyme deficiency only affects certain drugs); genes demonstrate different degrees of heterogeneity (polymorphism)
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what do the different parts of the nomenclature indicate in the example 'cytochrome P450 2D6*4'?
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cytochrome P450 = superfamily
2 = family D = subfamily 6 = isoenzyme: specific protein, allozyme is specific protein expressed from variant allele *4 = allelic variant: aspect of genetic variability, usually *1 is highest prevalence |
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what does the different designations of enzyme systems indicate?
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each have substrate specificity in that they metabolize a specific class or specific medications of a specific class
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how much genetic material do 1st degree relatives share?
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1/2
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