Mahogany
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I'm very confused with the single gene disorder questions on NBME 2. One question showed a pedigree with different cancers in the family down generations -- the cancers being Breast (age of onset (AOG) 28, 36 & 51), myxofibrosarcoma (AOG 48), medulloblastoma ( AOG 5) and rhabdomyosarcoma (AOG 8). The choices were:
anticipation, genetic heterogeneity, incomplete penetrance, multifactorial inheriatance and variable expressivity.
Another question was:
Female neonate has profound hypotonia. Only known complixn in pregnancy is polyhadramnios. Mother has lack of facial expression and weak muscles and claims no problems during childhood or infancy. What explains the difference between mother and child . . . anticipation, delayed age of onset, genetic heterogeneity, incomplete penetrance and pleiotropy.
I just really want to know the difference between genetic heterogeneity, pleiotropy and variable expressivity. And, is genetic heterogeneity the same as locus heterogeneity.
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| msyamp
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second one i go with anticipation.
first one i go with anticipation or variable expressivity?
genetic heterogenety is same as locus hetero genetiy.
it is said to be if you get the same disease by mutations at different genetic loci mutations in diff individuals.
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| msyamp
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variable expressivity is each patient may express all of the symptoms, or only a few
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| msyamp
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[left]pleiotropy is situation in which a single gene influences multiple phenotypic traits[/left]
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| reet
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pleiotrophy-- when single disease causing mutation affects mutiple organs.. example--MARFAN SYNDROME - involve periosteum, perichondrium,suspensary ligament of eye,Aorta,
Locus hetrogenety---when same disease phenotype can be caused by mutation in DIFFERENT loci. example-- OSTEOGENESIS IMPERFECTA ( 4 type s collagen)
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| drk1980
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Even the first Q(Li-Fraumeni syndrome i think?) is "anticipation" IMO(from the choices).
Variable expressivity concerns with different levels of expression of the same disease. Eg NF, some patients develop all the problems ie. lisch nodules,schwannoma's etc and others will show only cafe-au lait spots in their entire lifetime.
kindly correct me
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| msyamp
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here P53 deletion is being variably expressed. and hence the patients are getting different cancers.
but you can also be right. but even anticipation means increased severity of a single genetic disorder.like huntington's becomes earlier onset as generations go.
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| drk1980
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Genetic Anticipation and Li-Fraumeni Syndrome
Tracy Costello, Ph.D., Chris Amos, Ph.D.
Genetic anticipation is defined as a decrease in age of onset or increase in severity as the disorder is transmitted through subsequent generations. Anticipation effects have been observed in numerous complex diseases including mental disorders (e.g. Schizophrenia, Bipolar Disorder) and cancers (Li-Fraumeni Syndrome, Leukemia). Specifically, anticipation in several diseases including Huntington's Disease, Myotonic Dystrophy and Fragile X Syndrome were shown to be caused by expansion of triplet repeats. We developed family-based likelihood modeling approaches to assess anticipation that appropriately model the underlying transmission of the disease gene and penetrance function. These methods can be applied in extended families that should increase the power to detect anticipation compared with existing methods based only upon parents and children. To evaluate the new methods, we performed extensive simulation studies and validated the method with data from an M. D. Anderson Li-Fraumeni cohort. Results of analyses of the LFS cohort with the likelihood based method showed evidence for both a generational effect a residual genetic effect after accounting for effects of the tumor suppressor gene, p53. Further analyses to verify a reported gender effect are ongoing.
http://www.mdanderson.org/departments/epidemiolog...
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| msyamp
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thanks. i got it.
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| aarya
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in kaplan notes, Li-Fraumeni syndrome is explained on the basis of cigarrete smoke causing mutations on TP53 gene, which results in damaged cells and hence various noninherited cancers.........so can the correct choice in the 1st ques above not be..........multifactorialinheritance
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| nadiabarati
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the first Q is genetic heterogeneity, the second is anticipation
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| nadiabarati
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oh sorry never genetic heterogeneity in first Q
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| mjl1717
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#2) is anticipation #1) Ill guesss multifactorial inheritance (Idont think cancers can all be linked as the SAME disease) someone prove me wrong [Also as far as incomplete penetrance there is NOTHING incomplete about these cancers!]
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| usmle99
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retinoblastoma and familial breast cancer are examples of incomplete penetrance in kaplan notes
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| mjl1717
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can anyone else shed light on this q?
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| doc179
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I just know that ..as usmle99 said ...those are the examples for incomplete penetrance and if that individual has a secondary influence then he will get that cancer..for example if that person is irradiated or anything that causes cancer then this guy will surely show cancer phenotypically
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| aarya
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as mjl 1717 has pointed out above , all cancers cannot be taken as same disease entity, had the ques above mentioned only 1 particular type of cancer (like breast ca or retinoblastoma) in the subsequent generations, incomplete penetrance would have fitted the description.
since this is not the case, i feel "multifactorial inheritance"is a better choice here
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| mjl1717
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well at least be able to define the genetic terms and have examples
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| pearljam59
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Regarding the pedigree question (first one)...the first line of the question states, " A syndrome associated with various neoplasms..."
To me, that is saying ONE particular genotype. So the fact that you have a different nature and severity phenotypes would arguably make the answer variable expression.
It cannot be anticipation because the age of onset starts at 28 and 36 in generation I then 51 and 48 to a couple members in generation II and finally to 5 and 8 to two more members of generation III.
It cannot be genetic heterogeneity because the end product would have to be the same disease.
It cannot be incomplete penetrance because people ARE affected with the syndrome.
It cannot be multifactorial inheritance because well I do not have a good reason but I think it is too broad of an answer. The question has to do with a syndrome that seems to be inherited AR which to me would not be a good answer.
Comments?!
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| krsna
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but isnt variable expression a varibility in the severity of expression of the disease....pearljam59 pls make it a bit more clear.
thnx
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