1-33 Clinical Applications: Cystic Fibrosis and Fragile X Syndrome Flashcards Preview

MSI Unit I > 1-33 Clinical Applications: Cystic Fibrosis and Fragile X Syndrome > Flashcards

Flashcards in 1-33 Clinical Applications: Cystic Fibrosis and Fragile X Syndrome Deck (44)

Current clinical lab tests for cystic fibrosis

detection of delta F508 mutation via PCR then run on gel to separate sequences

-linkage with intragenic markers
-whole genetic sequencing
-sanger sequencing



based on luminscence

Pyrosequencing - produces light when nucleotide encorporated and sequence extended.

Nucleotides are dispensed one at a time in a defined order. Excess are removed before dispensing next one.

If the complement of the nucleotide dispensed is present int eh template, light is produced.

Light produced is converted into a peak (pyrogram). Height = proportional to number of nucleotides incorporated.


current clinical lab tests for fragile x

PCR has difficulty amplifying the full mutation due to allelic dropout.

southern blot is an option, it detects the expansion in the high premutation and full mutation.


premutation fragile x carryin females with show southern blot bands

4 bands. as they have methylated and unmethylated sequences on both the active and inactive X. All four sequecnes contain differnt numbers of bases


MOI of cystic fibrosis

autosomal recessive with significant allelic heterogeneity


MOI of fragile x

disease caused primary by dynamic mutations at a chromosomal fragile site

but it is best modeled as x-linked dominant disease with reduced penetrance for females


fragile x is caused by

disease caused by triplet repeat expansion


CF is characterized by

pancreatic insufficiency
Chronic lung disease (mucus dehydrated)

blockage of chloride channels produces salty sweat


what is allelic heterogeneity?

the same disease (CF) is caused by different mutations of the same gene


fragile X is the most

common cause of inherited mental retardation


presentation of fragile x

retardation, large ears, long face


99% of fragile X cases are caused by

CGG triplet repeats in non-coding, fragile region and methylation of FMR1 gene


almost all boys with CF will be

infertile due to vas deferens issue


mutations at the gene CFTR are also found in about half of patients with

congenital bilateral absence of vas deferens


Mutations of DMD?



CF mutations?

point mutations


classic cystic fibrosis is characteerized by

progressive chronic lung disease and pancreatic insufficicency


CF results from a deficiency in the

CFTR protein, which acts as a chloride ion channel in endocrine cells


the lungs in CF become colonized by..

the mucus of the lungs gets thick, lungs get colonized by P.aeruginosa and other bacteria - this leads to an immune response that further degrades pulmonary function


one of the earliest signs of CF?

the meconium plug detected in fetal imaging


a straightforward way to detect delta F508?

run the PCR product on acylamide gel which can detect the 3bp difference in aplicon length


CF gene sequencing of a CF patient should detect

two CF mutations (homo or compound hetero)


What makes Fragile X MOI odd?

although it is X-linked and seen more often in boys, it is only seen twice as much.


carrier females

some, but not all are symptomatic


the best MOI model of fragile x

x-linked dominant with a reduced penetrance (80% in males, 30% in females)


it is thought that the disease penetrance of fragile x

is dependant on the x-inactivation pattern in the critical brain tissues


cause of FRAXA?

CGG repeat in the FMR1 gene


the expansion from premutation to mutation only occurs

during transmission from a FEMALE, but not a male, premutation carrier


inhertitance of the full mutation?

the full mutation is not inherited from premutation males, selection against sperm carryin gthe full mutation


where is the risk of having a child with FRAXA?

is in the children of of premutation carrier females and
grandchildren of premutation males.


how should you counsel a patient who is a fragile X normal transmitting male

that he has a 1/3 chance of developing FXTAS


a modest increase in size of the marker

normal transmitting male


Fragile X demonstrates

anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation.


triplet repeats account for the phenomenon of



cystic fibrosis is best analyzed with...

microarray to detect deletions


Which of the following is NOT a characteristic of newborn screening?
a. biochemical disorder
b. disease confirmation
c. easy to perform
d. high sensitivity
e. high specificity

newborn screening is not disease confirmation. a diagnostic test is needed to confirm.


joyce is from population in which autosomal recessive disorder is in HW equilibrium and has a birth incidence of 1/1,300. her husband is phenotypically normal but has a newphew effected wtih the disorder. Since joyce is pregnant, what do you tell her is the risk to the fetus?



HD is due to a _____ of function, FRAXA is due to a _____ of function

HD - gain of function
FRAXA - loss of function due to expansion of a CGG repeat.


Bernard and his pregnant wife, Joan, are phenotypically normal. Joan's brother is affected with a rare disorder. Which of the following modes of inheritance would result in the highest risk that Joan's fetus will manifest (i.e. be affected with) this disorder?

A. Autosomal recessive

B. Autosomal dominant.

C. X-linked benign recessive

D. X-linked dominant

E. X-linked genetic-lethal recessive

C. Since Joan is phenotypically normal, autosomal or X-linked dominant inheritance is unlikely. If autosomal recessive, Bernard would also have to be a carrier, which is unlikely. If X-linked recessive benign, Joan's carrier risk is ½ and the chance that the fetus is affected would be ½ x ½ x ½ = 1/8. Due to Haldane's Rule, if it was an X-linked lethal, the risk would be less than 1/8.


What is the approximate risk of sickle cell disease (SCD) in a child from a couple, both of whom have first cousins with SCD?

Each has a 1/ 4 carrier risk, multiplied by the 1/ 4 risk they both pass it on gives 1/64.

one of grandparents has it
1/2 chance parent carries
1/4 chance they carry

1/4*1/4*1/4 = 1/64


Match the situation described with the term that best defines it. There are over 2,000 disease-causing mutations already described for cystic fibrosis.
Selected Answer:

A. Locus heterogeneity

B. Anticipation

C. New mutation

D. Allelic heterogeneity

E. Non-penetrant



PCR of fragile x

has difficulty amplifying the full mutation and larger pre-mutations

allelic dropout can also happen


southern blot of fragile x

can detect the expansion in the high premutation and full mutation ranges until about 200 repeats


how many bands will premutation fragile x females show on southern blot?

4 - methylated and unmethylated sequences of both active and inactive X.

Decks in MSI Unit I Class (52):