Molecular

Question 1

4 benifits of MLPA for Duchenne Muscular Dystrophy testing

Answer 1

• Specific allele detection
• Copy number detection (deletion/duplication)
• Methylation status
• Carrier screening

Question 2

Percentage risk for gonadal mosaicism in Duchenne Muscular Dystrophy

Answer 2

Risk of gonadal mosaism is 15%

Question 3

Risk of germline mosaisism and recurrance risk in after a woman who has an afected child, is not found to have a DMD variant

Answer 3

Risk of gonadal mosaism X chance of transmitting

15% X 1/2 = 7% Recurrance risk

Question 4

The majority of cases of achondroplasia are caused by this variant

Answer 4

• FGFR3*
  p. Gly380Arg

99% G>A transistion

1% G>C transversion

80% de novo (paternal)

Question 5

Juvanille repeats in Huntington Disease >60 repeats: an increase of > 7 repeats in the next generation is usually inherited from which parent

Answer 5

Paternal

Question 6

WHat is the benifit of using linked markers to determine an at risk grandchild for Huntington’s disease

Answer 6

Linked markers look at “at risk” alleles and this does not change the parental risk with an at risk grandchild.

Question 7

What is the smallest number of repeats that have been documented to expand in a Fragile X carrier?

Answer 7

56 CGG repeats

Question 8

What number of repeats in a Fragile X carrier is amost 100% likly to expand in the next generation

Answer 8

100 CGG repeats

Question 9

Modality used to identify Fragile X carriers and those affected

Answer 9

Triple primed PCR with methylation (extra step)

Question 10

What is the signifigance of the poly T tract in CF mutation carriers

Answer 10

The poly T tract in intron 8 results in skipping of exon 9

resulting in a dysfuctional CFTR transcript or no transcript

the 5T allele results in 90% of transcripts without exon 9

p.Phe508del is a LD with the 9T Allele

Question 11

What are the limitation of Sanger Sequencing

Answer 11

Can only analyze one sample at a time

cannot detect large deletions and duplications

not good for large repeat expansions

Allelic dropout

missed low level mosaicism

Question 12

Most individuals who are RhD negative have a complete ______ of the gene

Answer 12

Deletion

Question 13

Why is the mother sample needed for genetic testing for hemolytic Disease of the newborn

Answer 13

No maternal sample–> hard to interprate

could represent a true Rh positive fetus

could also represent Rh neg fetus with intact D gene or at least some portion of the D gene

Therefore the maternal sample is needed

Question 14

Chromosomal microarrays are limited and cannot detect

Answer 14

Balanced translocations

Inversions

Polyploidy

UPD with fully parental heterodisomy

Question 15

What is the benifits of using SNP genotyping with CGH array

Answer 15

Can be used to detect

• Consangunity
• Uniparental Disomy
• Long continuous stretches of homozygosity (>5Mb)

Question 16

What are the 4 possible genetypes detected by SNP array in a sample that shows a duplication?

Answer 16

1. BBBB
2. BBBA
3. AAAB
4. AAAA

Question 17

What is the Log2Ratio found for a duplication on aCGH

Answer 17

+0.6

Question 18

ACMG recommends array based technology as the first tier for?

Answer 18

1. Developmental delay and/or cognitive impairment DD/DI)
2. Autism Spectrum Disorder (ASD/PDD)
3. Multiple congenital anomalies
4. Epilepsy

Question 19

What are advantages of using microarray vs karyotype to analyze products of conception

Answer 19

CMA adds 10% sensitivity for miscariages

Finds pathogenic microdeletions and duplications

No need for culture–> faster TAT

Question 20

In general, microscopically visable CNVs > ____ are reportable

Answer 20

>3-5Mb

Question 21

Uncle-neice union

coefficient of consanguinity ((F)

Answer 21

1/4

Question 22

Uncle-neice union coefficient of inbreeding

Answer 22

1/8

Question 23

First cousins

coefficient of consanguinity (F)

Answer 23

1/8

Question 24

First cousins coeeficient of inbreeding

Answer 24

1/16

Question 25

First cousins once removed coefficient of consanguinity (F)

Answer 25

1/16

Question 26

First cousins once removed coefficient of inbreeding

Answer 26

1/32

Question 27

What type of responders to codeine may get the drug to fast leading to respiratory distress

Answer 27

Ultrarapid-responders *CYP2D6* Codeine--\>active form of morphine N.Africans, Ethiopians, Saudi Arabians (16-28%)

Question 28

*CYPC19* poor responders to this medication cannot prevent clots, may need to take another drug

Answer 28

Clopidogrel (Plavix)

Question 29

Poor metabolizers to Warfarin with these two mutations may be at risk for bleeding

Answer 29

* CYP2C9* * VKORC1* poor metabolizer- need to reduce dose ultrarapid metabolizer- need to increase dose

Question 30

Specific amino acid substitions in these genes may interfere with binding of this drug to kinase used to treat CML and GIST (KIT mutations)

Answer 30

Imatinib Mesylate *CYP3A4 and CYP3A5* T3151I

Question 31

HLA-B\*5701 variants and Abacavir may put patient at increase risk for life threatening condition

Answer 31

Steven-Johnson Syndrome

Question 32

The FDA recommends *TPMT* genotyping or phenotyping before starting this medications

Answer 32

Azathioprine This allows patients who are at increased risk for toxicity to be identified and for the starting dose of azathioprine to be reduced, or for an alternative therapy to be used Azathioprine is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), the major active metabolites. Thiopurine S-methyltransferase (TPMT) inactivates azathioprine, leaving less parent drug available to form TGNs. An adverse effect of azathioprine therapy is bone marrow suppression, which can occur in any patient, is dose-dependent, and may be reversed by reducing the dose of azathioprine

Question 33

About what percentage of carriers of *DMD* have clinically signifigant cardiomyopathy

Answer 33

about 8%

Question 34

What are the various ways a female with features of DMD can arise? (5)

Answer 34

1. Skewed X- inactivation 2. Turner syndrome 45, X 3. Balanced X-autosome translocation (non-translated X is inactivated and DMD variant is on translocated active X) 4. Uniparental disomy X 5. Compound heterozygosity

Question 35

What is the residual risk of a mother with negative genetic analysis for DMD having second son with DMD?

Answer 35

Residual Risk of 7% Germline mosaisim up to 10-15% in mothers with negative genetic analysis

Question 36

Acoording to the DMD practice guildines what is the first test that should be ordered if one is considering a diagnosis of DMD?

Answer 36

CPK If not elevated DMD is not likly and should consider an alternative diagnosis Order of evaluation CPK--\>DMD CNV analysis--\>DMD sequence--\>Muscle biopsy

Question 37

what are the limitations of CNV by MLPA for DMD?

Answer 37

Allelic dropout False positives: single exon deletion due to SNV under probe--\>should confirm by sequencing Limited by the amount of probes per reaxn.

Question 38

Eteplirsen induces skipping of what exon for DMD tx.

Answer 38

exon 51

Question 39

These repeats within the CGG repeats of FMRP result in less liklihood of CGG repeating in the next generation

Answer 39

AGG repeats