Disorders of Unstable Repeat Sequences Flashcards by Josh Klonoski

Which one of the following statements regarding instability of unstable repeat sequences is correct?
A.The instability may lead to an increase or a decrease in repeat length intergenerationally or somatically.
B.All unstable repeat disorders are autosomal dominant.
C.All unstable repeat disorders are caused by trinucleotide repeat expansion.
D.Expansion of unstable repeats are loss-of-function changes due to methylation
E.None of the above.

A.The instability may lead to an increase or a decrease in repeat length intergenerationally or somatically.

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Which one of the following disorders is NOT caused by the expansion of unstable repeat sequences?
A. Duchenne muscular dystrophy
B. Fragile X syndrome
C. Friedreich ataxia
D. Huntington disease
E.Myotonic dystrophy type 1
F.Myotonic dystrophy type 2

A. Duchenne muscular dystrophy

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Which one of the following disorders is NOT caused by the expansion of trinucleotide repeat sequences?
A. Fragile X syndrome
B. Friedreich ataxia
C. Huntington disease
D.Myotonic dystrophy type 1
E.Myotonic dystrophy type 2
F.All of the above
G.None of the above

E.Myotonic dystrophy type 2

CCTG tetranucleotide repeat

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Which one of the following disorders of unstable repeat expansion does NOT exhibit dominant inheritance patterns?
A. Fragile X syndrome
B. Friedreich ataxia
C. Huntington disease
D.Myotonic dystrophy type 1
E.Myotonic dystrophy type 2
F.All of the above
G.None of the above

B. Friedreich ataxia

FA - autosomal recessive

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Which one of the following disorders of unstable repeat expansion has the repeat sequence in the coding region?
A. Fragile X syndrome
B. Friedreich ataxia
C. Huntington disease
D.Myotonic dystrophy type 1
E.Myotonic dystrophy type 2
F.All of the above
G.None of the above

C. Huntington disease

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6 yo boy with epilepsy and grandfather with Huntington. Testing of grandfather showed 44 repeat of CAG in HTT. The boy’s father is asymptomatic with 52 copies. Huntington test showed 25/66 CAG repeats in the boy. Which one of the following would be the most appropriate interpretation of the allelic difference between the grandfather, the father, and the boy?
A. Anticipation
B. Epistasis
C.Lab error with wrong specimens
D. PCR artifacts
E. Pleiotropy
F.None of the above

A. Anticipation

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Child with tremor and epilepsy. Chromosome microarray found a 300-kb interstitial deletion on 4p16.3 including the HTT gene. Trinucleotide repeats test for Huntington disease on the patient detected homozygous 26 CAG repeats. What would be the most appropriate interpretation of the chromosome microarray results?
A. Normal
B.Unknown clinical significance, likely benign
C. Unknown clinical significance
D.Unknown clinical significance, likely pathogenic
E. Pathogenic

C. Unknown clinical significance

A normal allele is 6–26 repeats; a gray zone allele 26–35; a reduced penetrance allele 36–39; and a full mutation ≥40.

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The doctor ordered trinucleotide repeats test for Huntington disease. The results showed that the patient had compound heterozygous 30/65 copies of CAG in the HTT gene. When a genetic counselor saw this family, she mentioned that the likelihood that the patient inherited the mutated copy from his biological father was:
A. 10%
B. 30%
C. 50%
D. 60%
E. 90%

E. 90%

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In which part of the HTT gene is the trinucleotide unstable repeat for Huntington disease is located?
A. Promoter
B. 5′ UTR
C. Intron
D. Exon
E. 3′ UTR

D. Exon

first exon

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Which one of the following genetic alterations in the HTT gene causes Huntington disease?
A. Point mutations
B. in/del
C.(CAG)n repeats in an intron
D.(CAG)n repeats in an exon
E.(CGG)n repeat in an intron
F.(CGG)n repeat in an exon
G.(CTG)n repeat in an intron
H.(CTG)n repeat in an exon

D.(CAG)n repeats in an exon

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Which one of the following molecular genetic assays is the most appropriate for the diagnosis of Huntington disease in clinical laboratories?
A. Chromosome karyotype
B. Chromosome microarray (CMA)
C.Multiplex ligation-dependent probe amplification (MLPA)
D.PCR/capillary electrophoresis and Southern blot
E. PCR/capillary electrophoresis
F. Triplet repeat–primed PCR

D.PCR/capillary electrophoresis and Southern blot

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Prenatal counseling. The wife had 24/35 copies of CAG repeats in the HTT gene for Huntington disease (HD), which were not interrupted by CCG repeats. She was 32 years old and had no HD symptoms. Which one of the following would most likely be the risk of HD in her children?
A. 0.5%
B. 30%
C. 50%
D. 80%
E. 100%

A. 0.5%

A normal allele is 6–26 repeats; a gray zone allele 26–35; a reduced penetrance allele 36–39; and a full mutation ≥40.

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Prenatal testing. The husband has 24/35 copies of the CAG repeats in the HTT gene for Huntington disease (HD), which are not interrupted by the CCG repeats. He is 42 years old and has no HD symptoms. Which one of the following would most likely be the risk of HD in his children?
A. 0.5%
B. 10%
C. 50%
D. 80%
E. 100%

A. 0.5%

A normal allele is 6–26 repeats; a gray zone allele 26–35; a reduced penetrance allele 36–39; and a full mutation ≥40.

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The husband is 42 years old and has no symptoms of HD. A molecular test detects that he has 16/25 CAG repeats. What is the clinical significance of the results?
A.The husband may not develop Huntington disease.
B.The husband does not have Huntington disease. But his children will be at risk.
C.The husband may develop Huntington disease. His children have 10% to 50% chance of having HD.
D.The husband has Huntington disease. His children have 50% chance of having HD.
E.None of the above.

A.The husband may not develop Huntington disease.

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The results showed that BJ has 20/38 copies of CAG in the HTT gene. What would be the interpretation of this result?
A.BJ had normal alleles.
B.BJ had a gray zone mutation.
C.BJ had a premutation.
D.BJ had a full mutation.

C.BJ had a premutation.

A normal allele is 6–26 repeats; a gray zone allele 26–35; a reduced penetrance allele 36–39; and a full mutation ≥40.

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Molecular testing shows that he has 18/34 CAG repeats. What is the clinical significance of the results?
A.The husband does not have Huntington disease.
B.The husband does not have Huntington disease, but his children will be at risk.
C.The husband may develop Huntington disease, and his children have a 10%–50% chance of having HD.
D.The husband has Huntington disease, and his children have a 50% chance of having HD. E.None of the above.

B.The husband does not have Huntington disease, but his children will be at risk.

A normal allele is 6–26 repeats; a gray zone allele 26–35; a reduced penetrance allele 36–39; and a full mutation ≥40.

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Molecular testing shows that he has 19/38 CAG repeats. What is the clinical significance of the results?
A.The husband does not have Huntington disease.
B.The husband does not have Huntington disease, but his children will be at risk.
C.The husband may develop Huntington disease, and his children have a 10%–50% chance of having HD.
D.The husband has Huntington disease, and his children have a 50% chance of having HD. E.None of the above.

D.The husband has Huntington disease, and his children have a 50% chance of having HD.

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Molecular testing shows that he has 20/41 CAG repeats. What is the clinical significance of the results?
A.The husband does not have Huntington disease.
B.The husband does not have Huntington disease, but his children will be at risk.
C.The husband may develop Huntington disease, and his children have a 10%–50% chance of having HD.
D.The husband has Huntington disease, and his children have a 50% chance of having HD. E.None of the above.

D.The husband has Huntington disease, and his children have a 50% chance of having HD.

A normal allele is 6–26 repeats; a gray zone allele 26–35; a reduced penetrance allele 36–39; and a full mutation ≥40.

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Acknowledging the technical limitations of size analysis, the American College of Medical Genetics and Genomics (ACMG) supports which one of the following acceptable ranges for alleles with less than 50 repeats with Huntington disease clinical testing and as grading criteria for the College of American Pathology (CAP)/ACMG proficiency testing survey?
A.Consensus size ±1 repeats
B.Consensus size ±2 repeats
C.Consensus size ±3 repeats
D.Consensus size ±4 repeats
E.Consensus size ±5 repeats

B.Consensus size ±2 repeats

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Acknowledging the technical limitations of size analysis, the American College of Medical Genetics and Genomics (ACMG) supports which one of the following acceptable ranges for alleles with 50-70 repeats with Huntington disease clinical testing and as grading criteria for the College of American Pathology (CAP)/ACMG proficiency testing survey?
A.Consensus size ±1 repeats
B.Consensus size ±2 repeats
C.Consensus size ±3 repeats
D.Consensus size ±4 repeats
E.Consensus size ±5 repeats

C.Consensus size ±3 repeats

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Acknowledging the technical limitations of size analysis, the American College of Medical Genetics and Genomics (ACMG) supports which one of the following acceptable ranges for alleles with >70 repeats with Huntington disease clinical testing and as grading criteria for the College of American Pathology (CAP)/ACMG proficiency testing survey?
A.Consensus size ±1 repeats
B.Consensus size ±2 repeats
C.Consensus size ±3 repeats
D.Consensus size ±4 repeats
E.Consensus size ±5 repeats

D.Consensus size ±4 repeats

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The pathogenesis of Huntington disease is:
A. Activating mutation
B. Loss of function
C.Novel property on the protein
D.Novel property on the RNA
E.Novel property on the DNA
F. Overexpression

C.Novel property on the protein

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Mom diagnosed at 52 with Huntington disease with compound heterozygous 17/38 repeats the (CAG)n. What would be the chance her son has the same condition?
A. 1/2
B. 1/4
C. 10%
D. Up to 1%
E. Not predictable
F.None of the above

E. Not predictable

Allele sizes of 36–39 CAG repeats have been reported in both clinically affected and clinically unaffected individuals.
Therefore, it is not possible to predict the chance the son had the same condition

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Mom diagnosed at 52 with Huntington disease with compound heterozygous 17/38 repeats the (CAG)n. Son decided to be tested for Huntington’s disease and found out that he has 19/38 repeats. Son and his wife wanted to test their son for Huntington disease. Which one of the following actions would be the most appropriate response from the care provider?
A.Ordering the molecular genetic test for his son as the couple request
B.Explaining to the couple that it is better for their son to make his own decision when he grows up, since there are no preventive measures available for HD
C.Explaining to the couple that this clinic may not provide the test to the child, and referring the couple to another clinic
D.Explaining to the couple that the genetics laboratory in the hospital provides the test only to adults and that the clinic cannot find a lab to test the son
E.Explaining to the couple that insurance will not pay to test for children and that it is better for them wait until the son grows up

B.Explaining to the couple that it is better for their son to make his own decision when he grows up, since there are no preventive measures available for HD

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Mom diagnosed at 52 with Huntington disease with compound heterozygous 17/38 repeats the (CAG)n. Test results showed that son had 19/42 copies of the repeat. Son and his wife are 6 weeks pregnant and present for prenatal counseling. Which one of the following would be most appropriate next step in the workup? A. Ordering a molecular genetic test with CVS sample B. Ordering a molecular genetic test with amniocentesis sample C. Explaining to the couple it is their unborn child’s decision when he/she grow up since there are no preventative measures available for Huntington’s disease D. Explaining to the couple this clinic may not provide the test to prenatal samples, then refer the couple to another clinic E. Explaining to the couple the genetic laboratory in this hospital only provide the test to adults, but not prenatal samples F. Explaining to the couple the insurance won’t pay if it is for prenatal diagnosis

A. Ordering a molecular genetic test with CVS sample

Mother diagnosed with Huntington disease with compound heterozygous 17/40 (CAG)n. What is the chance her healthy adult son inherited the same condition? A. 1/2 B. 1/4 C. 10% D. Up to 1% E. Not predictable F. None of the above

A. 1/2

Daughter of uncle with 17/37 (CAG)n repeats and HD. Her dad subsequently tested as 17/35 but what was her risk before the test? A. 1/2 B. 1/4 C. 8% D. Not predictable E. None of the above

C. 8% There have been no reports of maternally transmitted alleles in this range producing offspring with affected alleles. This risk may be as high as 6%–10% for paternal alleles carrying a CAG repeat of 35.

Prenatal counseling with grandmother and father diagnosed by (CAG)n repeats of 19/43 and 17/61, respectively. CVS testing shows the fetus has 17/61 copies of the repeat. Which one of the following explanations would most likely be given to Jenny and her husband?A. The baby will develop Huntington symptoms in childhood or early adulthood. B. The baby will develop Huntington symptoms in the middle of adulthood. C. The baby will not develop Huntington symptoms. D. The pregnancy will most likely end in a miscarriage. E. It is not predictable whether the baby will develop Huntington symptoms because of the high frequency of somatic mosaicism.

A. The baby will develop Huntington symptoms in childhood or early adulthood. The fetus has an HTT allele with more than 60 CAG repeats, which is usually associated with juvenile onset of symptoms. Juvenile Huntington disease (HD) is defined by the onset of symptoms before age 20 years and accounts for 5%–10% of HD cases.

Prenatal counseling. Father has an HD FHx and his peripheral-blood sample was positive. Invasive prenatal diagnosis was elected. The molecular testing result with CVS sample is shown with 22/101 copies of the repeat. Which of the following molecular methods did the laboratory use for the testing? A. Southern blot B. Conventional PCR C. Triplet repeat–primed PCR D. Methylation study E. Sanger sequencing

C. Triplet repeat–primed PCR Triplet repeat–primed PCR (TP PCR) refers to amplify the CAG(n) repeat region in HTT for Huntington disease (HD) by PCR using three primers: a fluorescence-labeled forward primer, located upstream of the CAG(n) region, a chimeric reverse primer located partially within the CAG(n) region, and a reverse primer located downstream of the repeat region. The chimeric reverse primer hybridizes to multiple locations within the CAG(n) repeat region, creating PCR products of varying sizes. TP PCR provides a characteristic ladder on the fluorescence trace, enabling the rapid identification of large pathogenic repeats that cannot be amplified using flanking primers. Because the 5′ end of the reverse chimeric primer exactly matches the sequence 3′ of the CAG(n) region, this product is preferentially amplified.

Prenatal counseling. Father has an HD FHx and his peripheral-blood sample was positive. Invasive prenatal diagnosis was elected. The molecular testing result with aCVS sample showed 22/101 copies of the repeat. Which one of the results should be in the final report? A. Normal allele(s) B. Heterozygous intermediate allele C. Heterozygous reduced-penetrance allele D. Heterozygous full-penetrance allele E. Heterozygous juvenile-onset allele

E. Heterozygous juvenile-onset allelee

Prenatal counseling. Father has an HD FHx and his peripheral-blood sample was positive. Invasive prenatal diagnosis was elected. The molecular testing result with a CVS sample showed 22/101 copies of the repeat. Which one of the following would most likely be the predicted onset of HD symptoms if the fetus/patient develops symptoms? A. Infancy B. 18 years C. 40 years D. 60 years E. Unclear F. None of the above

B. 18 years

Which one of the following ranges is NOT acceptable for Huntington clinical testing as grading criteria for the CAP/ACMG proficiency testing survey? A. Consensus size ±2 repeats for alleles with <40 repeats B. Consensus size ±3 repeats for alleles with 40–50 repeats C. Consensus size ±3 repeats for alleles with 50–75 repeats D. Consensus size ±4 repeats for alleles with >75 repeats

B. Consensus size ±3 repeats for alleles with 40–50 repeats A normal allele is 6–26 repeats; a gray zone allele 26–35; a reduced penetrance allele 36–39; and a full mutation ≥40. < 50 Consensus size ±2 repeats 50 - 70 Consensus size ±3 repeats > 70 Consensus size ±4 repeats

Anticipation is a common phenomenon in the diseases caused by trinucleotide repeats, except in: A. Fragile X syndrome B. Friedreich ataxia C. Huntington disease D. Myotonic dystrophy E. Spinocerebellar ataxia

B. Friedreich ataxia

Anticipation is a common phenomenon in the diseases caused by trinucleotide repeats, except in: A. Fragile X syndrome B. Spinal muscular atrophy C. Huntington disease D. Myotonic dystrophy E. Spinocerebellar ataxia

B. Spinal muscular atrophy

The trinucleotide unstable repeat of the FXN gene for Friedreich ataxia is located in: A. Promoter B. 5′ UTR C. Intron D. Exon E. 3′ UTR

C. Intron FXN gene, specifically within intron 1 of the gene on chromosome 9q13. Normal individuals have 7-38 GAA repeats, while FRDA patients have 66 to over 1700 repeats.

Which one of the following genetic changes in the FXN gene causes the majority of cases of Friedreich ataxia? A. Point mutations B. in/del C. (CAG)n repeats in an intron D. (CAG)n repeats in an exon E. (CTG)n repeats in an intron F. (CTG)n repeats in an exon G. (GAA)n repeat in an intron H. (GAA)n repeat in an exon

G. (GAA)n repeat in an intron FXN gene, specifically within intron 1 of the gene on chromosome 9q13. Normal individuals have 7-38 GAA repeats, while FRDA patients have 66 to over 1700 repeats.

32 yo man with affected FA brother. His father passed in an MVA. What would be the risk for the development of Friedreich ataxia without further laboratory testing? A. <1% B. 8% C. 25% D. 50% E. 75% F. 100% G. Cannot predict

C. 25%

32 yo man with affected FA brother. His father passed in an MVA. Peripheral-blood testing showed 11/30 copies of GAA in the FXN gene. What is the most appropriate interpretation of the molecular result? A. He had two normal alleles and would not develop symptoms for Friedreich ataxia. B. He had one premutation allele, and would not develop symptoms for Friedreich ataxia. C. He had one full-mutation allele and would not develop symptoms for Friedreich ataxia. D. He had one full-mutation allele and would not develop symptoms for Friedreich ataxia. E. None of the above.

A. He had two normal alleles and would not develop symptoms for Friedreich ataxia.

32 yo man with affected FA brother. His father passed in an MVA. Peripheral-blood testing showed 20/630 copies of GAA in the FXN gene. What is the most appropriate interpretation of the molecular result? A. He had two normal alleles and would not develop symptoms for Friedreich ataxia. B. He had one premutation allele, and would not develop symptoms for Friedreich ataxia. C. He had one full-mutation allele and would not develop symptoms for Friedreich ataxia. D. He had one full-mutation allele and would develop symptoms for Friedreich ataxia. E. He had one full-mutation allele and would develop early-onset Friedreich ataxia. F. None of the above.

C. He had one full-mutation allele and would not develop symptoms for Friedreich ataxia.

32 yo man with affected FA brother. His father passed in an MVA. Peripheral-blood testing showed 630/810 copies of GAA in the FXN gene. What is the most appropriate interpretation of the molecular result? A. He had two normal alleles and would not develop symptoms for Friedreich ataxia. B. He had one premutation allele, and would not develop symptoms for Friedreich ataxia. C. He had one full-mutation allele and would not develop symptoms for Friedreich ataxia. D. He had two full-mutation alleles and would develop symptoms for Friedreich ataxia. E. He had two full-mutation alleles and would develop early-onset Friedreich ataxia. F. None of the above.

D. He had two full-mutation alleles and would develop symptoms for Friedreich ataxia.

The pathogenesis of Friedreich ataxia is: A. Activating mutation B. Loss of function C. Novel property on the protein D. Novel property on the RNA E. Novel property on the DNA F. Overexpression

B. Loss of function ***corrected book says A but then states LOF

Which one of following spinocerebellar ataxias is NOT caused by expansion of unstable repeat sequences? A. Spinocerebellar ataxia type 1 B. Spinocerebellar ataxia type 2 C. Spinocerebellar ataxia type 3 D. Spinocerebellar ataxia type 4 E. All of the above F. None of the above

F. None of the above ***corrected by updates in science SCA4 is a repeat disorder Spinocerebellar ataxia type 4 - chromosome 16 ZFHX3 CGG repeats pt mutations: Spinocerebellar ataxia type 5 - SPTBN2 Spinocerebellar ataxia type 14 - PRKCG A significant portion of SCA types, including SCA1, SCA2, SCA3, and SCA6, are caused by an expansion of a small DNA sequence (nucleotide repeat

Which one of following spinocerebellar ataxias is inherited in autosomal dominant pattern? A. Spinocerebellar ataxia type 1 B. Spinocerebellar ataxia type 2 C. Spinocerebellar ataxia type 3 D. Spinocerebellar ataxia type 4 E. All of the above F. None of the above

E. All of the above SCA 1,2,3,4,6 and 7 are AD

Which one of following spinocerebellar ataxias is caused by expansion of unstable repeat sequences? A. Spinocerebellar ataxia type 1 B. Spinocerebellar ataxia type 3 C. Spinocerebellar ataxia type 6 D. Spinocerebellar ataxia type 7 E. All of the above F. None of the above

E. All of the above ATXN1 gene causes autosomal dominant spinocerebellar ataxia type 1 (SCA1). Expansion of the CAG repeats in the ATXN3 gene causes autosomal dominant spinocerebellar ataxia type 3 (SCA3). Expansion of the CAG repeats in the CACNA1A gene causes autosomal dominant spinocerebellar ataxia type 6 (SCA6). Expansion of the CAG repeats in one of the exons in the ATXN7 gene causes autosomal dominant spinocerebellar ataxia type 7 (SCA7)

Which one of following autosomal dominant spinocerebellar ataxias is caused by expansion of unstable repeat sequences located in an exon? A. Spinocerebellar ataxia type 1 B. Spinocerebellar ataxia type 2 C. Spinocerebellar ataxia type 6 D. Spinocerebellar ataxia type 7 E. All of the above F. None of the above

E. All of the above

The trinucleotide unstable repeats of the ATXN1 gene for autosomal dominant spinocerebellar ataxia type 1 is located in: A. Promoter B. 5′ UTR C. Intron D. Exon E. 3′ UTR

D. Exon

The pathogenic changes of the ATXN1 gene for spinocerebellar ataxia type 1 is: A. A CGG repeat in promoter B. A CGG repeat in 5′ UTR C. A CCTG repeat in an intron D. A CAG repeat in an exon E. A CTG repeat in 3′ UTR

D. A CAG repeat in an exon

The CAG repeats of the ATXN1 gene for autosomal dominant spinocerebellar ataxia type 1 codes for: A. Alanine B. Arginine C. Glutamine D. Histidine E. Proline

C. Glutamine

Man with affected brother with AD SCA. Father died in MVA. The medical geneticist ordered trinucleotide repeat tests for spinocerebellar ataxia type 1. The results showed that BJ had 20/120 copies of CAG in the ATXN1 gene without CAT interruption. Which one of the following would be the most appropriate interpretation of this molecular result? A. He had an intermediate allele and would not develop symptoms for spinocerebellar ataxia type 1. B. He had a reduced penetrance allele, and might develop symptoms for spinocerebellar ataxia type 1. C. He had a full mutations allele, but he would not develop symptoms for spinocerebellar ataxia type 1 but is a carrier. D. He had a full mutations allele and would develop symptoms for spinocerebellar ataxia type 1. E. None of the above.

D. He had a full mutations allele and would develop symptoms for spinocerebellar ataxia type 1. 40-50 repeats in the ATXN1 gene tend to develop symptoms in mid-adulthood, while those with more than 70 repeats typically experience symptoms in their teens An allele with 39 CAG repeats without the CAT repeat interruptions has the lowest number of repeats to be associated with symptoms.

Clinical history of myotonic dystrophy. Which of the following genetic assays would be the most appropriate one to confirm the diagnosis in this patient? A. Next-generation sequencing B. Sanger sequencing C. Targeted mutation analysis D. Triplet repeat–primed PCR assay E. None of the above

D. Triplet repeat–primed PCR assay

Which one of the following genes is associated with myotonic dystrophy type 1? A. DMPK B. FXN C. FMR1 D. HTT E. ZNF9

A. DMPK

The pathogenesis of myotonic dystrophy type 1 is: A. Loss of function B. Novel property on the protein C. Novel property on the RNA D. Novel property on the DNA E. Overexpression

C. Novel property on the RNA binding of the CGG repeats to RNA-binding proteins. Many of the RNA-binding proteins “quenched” by the excessive number of CGG repeats are regulators of splicing. More than a dozen distinct pre-mRNAs have been shown to have splicing alterations in MD1, including cardiac troponin T and insulin receptor.

The trinucleotide unstable repeat sequence in DM1 for myotonic dystrophy 1 is located in: A. Promoter B. 5′ UTR C. Intron D. Exon E. 3′ UTR

E. 3′ UTR Myotonic dystrophy, specifically types 1 (DM1) and 2 (DM2), are caused by repeat expansions in specific genes. DM1 is caused by a CTG repeat expansion in the 3' UTR DMPK gene on chromosome 19q13. DM2, on the other hand, is caused by a CCTG repeat expansion in intron 1 CNBP gene (also known as ZNF9) on chromosome 3q21.

The pathogenic changes of the DMPK gene for myotonic dystrophy type 1 is: A. A CAA repeat B. A CAG repeat C. A CCTG repeat D. A CGG repeat E. A CTG repeat

E. A CTG repeat CTG = Leucine

The results showed that she had 12/30 copies of CTG in the DM1 gene. Which one of the following would be the most appropriate interpretation of this molecular result? A. She had two normal alleles and would not develop symptoms for MD1. B. She had a mutable normal (premutation) allele and would not develop symptoms for MD1. C. She had a full-penetrance allele, but she would not develop symptoms for MD1 as a carrier. D. She had a full-penetrance allele and would develop symptoms for MD1. E. None of the above.

A. She had two normal alleles and would not develop symptoms for MD1..

The results showed that she had 12/45 copies of CTG in the DM1 gene. Which one of the following would be the most appropriate interpretation of this molecular result? A. She had two normal alleles and would not develop symptoms for MD1. B. She had a mutable normal (premutation) allele and would not develop symptoms for MD1. C. She had a full-penetrance allele, but she would not develop symptoms for MD1 as a carrier. D. She had a full-penetrance allele and would develop symptoms for MD1. E. None of the above.

B. She had a mutable normal (premutation) allele and would not develop symptoms for MD1.

The results showed that she had 24/75 copies of CTG in the DM1 gene. Which one of the following would be the most appropriate interpretation of this molecular result? A. She had two normal alleles and would not develop symptoms for MD1. B. She had a mutable normal (premutation) allele and would not develop symptoms for MD1. C. She had a full-penetrance allele, but she would not develop symptoms for MD1 as a carrier. D. She had a full-penetrance allele and would develop symptoms for MD1. E. None of the above.

D. She had a full-penetrance allele and would develop symptoms for MD1.

Prenatal counseling with maternal FHx. Testing of the mother showed she had MD1. Testing of the amniotic fluid showed that the fetus had 24/1200 copies of CTG in the DM1 gene. Which one of the following would be the most appropriate interpretation of this molecular result? A. The fetus had two normal alleles and would not develop symptoms for MD1. B. The fetus had a mutable normal (premutation) allele and would not develop symptoms for MD1. C. The fetus had a full-penetrance allele, but would not develop symptoms for MD1. D. The fetus had a full-penetrance allele and would develop symptoms for MD1. E. The fetus had a full-penetrance allele and would develop symptoms for MD1 early in life. F. None of the above.

E. The fetus had a full-penetrance allele and would develop symptoms for MD1 early in life. abnormal test results do not predict the age at onset or severity of the disease because of the overlap of CTG repeat length associated with the three phenotypes.The fetus had one normal allele and one full-penetrance allele associated with congenital MD1. Therefore, he/she would develop symptoms for congenital MD1.

Prenatal counseling with maternal FHx. Testing of the mother showed she had MD1 with DMPK compound heterozygosity of 12/99. CVS testing showed that the fetus had >1000 copies of CTG in the DMPK. Which one of the following would be the most appropriate interpretation of this molecular result? A. Reduced penetrance B. Mild C. Classic D. Congenital E. Not predictable

D. Congenital Congenital at >1000 CTG repeats

Neonatal death with severe hyptonia and respiratory complications. Molecular testing showed 2600 copies of CTG in DMPK. Which of the following tests would be recommended as the next step in the work up of two normal appearing parents? A. Maternal DM1 testing followed by paternal B. Paternal molecular genetic test for myotonic dystrophy type 1 followed by maternal test C. Parental molecular genetic test for myotonic dystrophy type 1 D. Maternal molecular genetic test for myotonic dystrophy type 2 followed by paternal test E. Paternal molecular genetic test for myotonic dystrophy type 2 followed by maternal test F. Parental molecular genetic test for myotonic dystrophy type 2

A. Maternal DM1 testing followed by paternal individuals: normal allele 5–34; mutable normal (premutation) 35–49; full-penetrance allele >50. When a patient has more than 1000 copies of the repeat, he/she usually has congenital MD1.

Which one of genes is associated with myotonic dystrophy type 2? A. DMPK B. FXN C. FMR1 D. HTT E. ZNF9

E. ZNF9

The unstable repeat sequence in the ZNF9 (CNBP) gene for myotonic dystrophy type 2 is located in: A. Promoter B. 5′ UTR C. Intron D. Exon E. 3′ UTR

C. Intron intron 1

Myotonic dystrophy type 2 is characterized by myotonia and muscle dysfunction, and less commonly by cardiac conduction defects, cataracts, type 2 diabetes mellitus, and testicular failure. ZNF9 (CNBP) is the only gene in which mutation is known to cause myotonic dystrophy type 2. ZNF9 intron 1 contains a complex repeat motif, (TG)n(TCTG)n(CCTG)n. Which one of the repeat sequences is unstable and associated with Myotonic dystrophy type 2? A. CAA B. CCTG C. CTG D. TCTG E. All of the above F. None of the above

B. CCTG ZNF9 (CBNBP)

A diagnosis of myotonic dystrophy was made. Which one of following statements is correct? A. The mutation for myotonic dystrophy type 1 is located in the 5′ UTR of DMPK. B. The mutation for myotonic dystrophy type 2 is located in the 3′ UTR of ZNF9 (CNBP). C. Both Myotonic dystrophy type 1 and 2 are caused by trinucleotide repeat expansion. D. Next-generation sequencing may detect 99% of mutations in both DMPK and ZNF9. E. Children will have 50% chance of developing myotonic dystrophy.

E. Children will have 50% chance of developing myotonic dystrophy..

A diagnosis of myotonic dystrophy was made. Which one of the genetic tests would be the most appropriate to confirm the diagnosis in this patient? A. Chromosome microarray B. Next-generation sequencing C. PCR/capillary electrophoresis and Southern blot D. Sanger sequencing E. Targeted mutation analysis

C. PCR/capillary electrophoresis and Southern blot

The molecular genetic test of the DMPK gene revealed that she was compound heterozygosity for 12/99 repeats. CVS testing was performed and confirmed that the unborn boy had approximately 200 copies of the CTG repeats in DMPK. Which one of the following would be the most appropriate interpretation for the unborn boy? A. Reduced penetrance B. Mild C. Classic D. Congenital E. Not predictable

C. Classic

Molecular genetic testing revealed that the wife was compound heterozygous for 12/45 DMPK CTG repeats. Which one of the following would be the most appropriate interpretation for the wife? A. Normal B. Mutable normal C. Full mutation D. Congenital E. None of the above

B. Mutable normal normal allele 5–34; mutable normal (premutation) 35–49; full-penetrance allele >50. When a patient has more than 1000 copies of the repeat, he/she usually has congenital MD1

The most common congenital cause of ID is: A. Down syndrome B. Fetal alcohol syndrome C. Fragile X syndrome D. Turner syndrome E. None of the above

B. Fetal alcohol syndrome

The most common genetic cause of ID is: A. Down syndrome B. Fetal alcohol syndrome C. Fragile X syndrome D. Turner syndrome E. None of the above

A. Down syndrome

The most common cause of inherited mental retardation is: A. Down syndrome B. Fetal alcohol syndrome C. Fragile X syndrome D. Turner syndrome E. None of the above

C. Fragile X syndrome

The unstable repeat sequence in the FMR1 gene for fragile X syndrome is located in: A. Promoter B. 5′ UTR C. Intron D. Exon E. 3′ UTR

B. 5′ UTR

The unstable repeat sequence in the FMR1 gene for fragile X syndrome is: A. CAA B. CAG C. CGG D. CTG E. CCTG

C. CGG

Which one of the following is the pathogenesis of fragile X syndrome? A. Loss of function B. Novel property on the protein C. Novel property on the RNA D. Novel property on the DNA E. Overexpression

A. Loss of function

Molecular testing showed she had 29/189 CGG copies of the CGG repeat. Which one of the following would be the most appropriate interpretation of this molecular result? A. The wife did not have fragile X syndrome. B. The wife did not have fragile X syndrome, but her children would be at risk for premutation. C. The wife did not have fragile X syndrome, but she was at risk for premature ovarian failure, and her children would be at risk for fragile X syndrome. D. The wife had fragile X syndrome. E. None of the above.

C. The wife did not have fragile X syndrome, but she was at risk for premature ovarian failure, and her children would be at risk for fragile X syndrome. normal has 5–44 copies of the repeat, the intermediate allele (gray zone, inconclusive, borderline) allele 45–54 copies, the premutation 55–200 copies; and the full-mutation allele more than 200 repeats.

Molecular testing showed she had 29/62 CGG copies of the CGG repeat. Which one of the following would be the most appropriate interpretation of this molecular result? A. The wife did not have fragile X syndrome. B. The wife did not have fragile X syndrome, but her children would be at risk for premutation. C. The wife did not have fragile X syndrome, but she was at risk for premature ovarian failure, and her children would be at risk for fragile X syndrome. D. The wife had fragile X syndrome. E. None of the above.

C. The wife did not have fragile X syndrome, but she was at risk for premature ovarian failure, and her children would be at risk for fragile X syndrome.

Molecular testing showed she had 29/52 CGG copies of the CGG repeat. Which one of the following would be the most appropriate interpretation of this molecular result? A. The wife did not have fragile X syndrome. B. The wife did not have fragile X syndrome, but her children would be at risk for premutation. C. The wife did not have fragile X syndrome, but she was at risk for premature ovarian failure, and her children would be at risk for fragile X syndrome. D. The wife had fragile X syndrome. E. None of the above.

B. The wife did not have fragile X syndrome, but her children would be at risk for premutation. normal has 5–44 copies of the repeat, the intermediate allele (gray zone, inconclusive, borderline) allele 45–54 copies, the premutation 55–200 copies; and the full-mutation allele more than 200 repeats.

Molecular testing showed she had 29/48 CGG copies of the CGG repeat. Which one of the following would be the most appropriate interpretation of this molecular result? A. The wife did not have fragile X syndrome. B. The wife did not have fragile X syndrome, but her children would be at risk for premutation. C. The wife did not have fragile X syndrome, but she was at risk for premature ovarian failure, and her children would be at risk for fragile X syndrome. D. The wife had fragile X syndrome. E. None of the above.

Molecular testing showed she had 29/42 CGG copies of the CGG repeat. Which one of the following would be the most appropriate interpretation of this molecular result? A. The wife did not have fragile X syndrome. B. The wife did not have fragile X syndrome, but her children would be at risk for premutation. C. The wife did not have fragile X syndrome, but she was at risk for premature ovarian failure, and her children would be at risk for fragile X syndrome. D. The wife had fragile X syndrome. E. None of the above.

A. The wife did not have fragile X syndrome. normal has 5–44 copies of the repeat, the intermediate allele (gray zone, inconclusive, borderline) allele 45–54 copies, the premutation 55–200 copies; and the full-mutation allele more than 200 repeats.

Prenatal counseling. Molecular testing showed she had 29/240 CGG copies of the CGG repeat. Which one of the following would be the most appropriate interpretation of this molecular result? A. The wife did not have fragile X syndrome. B. The wife did not have fragile X syndrome, but her children would be at risk for premutation. C. The wife did not have fragile X syndrome, but she was at risk for premature ovarian failure, and her children would be at risk for fragile X syndrome. D. The wife had fragile X syndrome. E. None of the above.

D. The wife had fragile X syndrome.

Prenatal counseling at 6 weeks. Molecular testing showed she had 29/240 CGG copies of the CGG repeat. Which one of the following would be the most appropriate recommendation to the family? A. NIPT B. CVS prenatal testing C. Amniotic prenatal testing D. Expansion by the father, no need for further testing E. None of the above

C. Amniotic prenatal testing Chorionic villus sampling (CVS) and amniotic fluid can be used for prenatal diagnostic testing. But because methylation is not fully established at the time of CVS, the appearance of full mutations examined by a methylation-specific method may vary in CVS as compared with blood and amniocytes. So it is an acceptable option to omit methylation analysis entirely when testing CVS specimens. In the minor fraction of CVS cases with a result that is ambiguous between a large premutation and a small full mutation by size criteria alone, a follow-up amniocentesis may be required.

A CVS sample was tested for the repeat. The results detected a single unmethylated allele with approximately 500 copies of the repeat. Which one of the following would be the clinical significance of the results? A. The unborn child would not have fragile X syndrome. B. The unborn child would not have fragile X syndrome, but he would be at risk for fragile X–associated tremor/ataxia syndrome (FXTAS). C. The unborn child would not have fragile X syndrome, but he would have fragile X–associated tremor/ataxia syndrome (FXTAS). D. The unborn child would have fragile X syndrome. E. None of the above.

D. The unborn child would have fragile X syndrome.

A CVS sample was tested for the repeat. The results detected a single unmethylated allele with approximately 200 copies of the repeat. Which one of the following would be the clinical significance of the results? A. The unborn child would not have fragile X syndrome. B. The unborn child would not have fragile X syndrome, but he would be at risk for fragile X–associated tremor/ataxia syndrome (FXTAS). C. The unborn child would not have fragile X syndrome, but he would have fragile X–associated tremor/ataxia syndrome (FXTAS). D. The unborn child would have fragile X syndrome. E. The clinical implication was unclear and follow up amniocentesis may be required F. None of the above.

E. The clinical implication was unclear and follow up amniocentesis may be required

A CVS sample was tested for the repeat. The results detected a single unmethylated allele with approximately 150 copies of the repeat. Which one of the following would be the clinical significance of the results? A. The unborn child would not have fragile X syndrome. B. The unborn child would not have fragile X syndrome, but he would be at risk for fragile X–associated tremor/ataxia syndrome (FXTAS). C. The unborn child would not have fragile X syndrome, but he would have fragile X–associated tremor/ataxia syndrome (FXTAS). D. The unborn child would have fragile X syndrome. E. None of the above.

B. The unborn child would not have fragile X syndrome, but he would be at risk for fragile X–associated tremor/ataxia syndrome (FXTAS) related. FXTAS occurs in both male and female premutation carriers, but the penetrance in individuals older than age 50 years is lower in females (16.5%) than in males (45.5%)

An amniotic sample was tested for the repeat. The results detected a single unmethylated allele with approximately 32/150 copies of the repeat. Which one of the following would be the clinical significance of the results? A. The unborn child would not have fragile X syndrome. B. The unborn child would not have fragile X syndrome, but she would be at risk for FMR-1related POI. C. The unborn child would not have fragile X syndrome, but she would have FMR-1related POI. D. The unborn child would have fragile X syndrome. E. None of the above

B. The unborn child would not have fragile X syndrome, but she would be at risk for FMR-1related POI.

The results came back and showed that she had 31/102 copies of the CGG repeat in the 5′ UTR region of the FMR1 gene. What was the approximate risk for her to have FMR1-related primary ovarian insufficiency? A. 1% B. 5% C. 20% D. 40% E. 60% F. 80%

C. 20%

A couple came to a genetics clinic for prenatal counseling when the wife was 10 weeks pregnant. She had 30/52 copies of the CGG repeat in the FMR1 gene. Subsequent testing found that the husband had 100 copies. Prenatal ultrasound showed that the fetus was a female. What diseases would the unborn daughter be at risk to have? A. Fragile X syndrome B. FMR1-associated tremor/ataxia syndrome (FXTAS) C. FMR1-related primary ovarian insufficiency (POI) D. A and B E. B and C F. A, B, and C G. None of the above

E. B and C Although anticipations occur through both maternal and paternal transmissions, it observed much more often in maternal transmissions

A couple came to a genetics clinic for prenatal counseling when the wife was 10 weeks pregnant. She had 30/52 copies of the CGG repeat in the FMR1 gene. Subsequent testing found that the husband had 30 copies. Prenatal ultrasound showed that the fetus was a female. What diseases would the unborn daughter be at risk to have? A. Fragile X syndrome B. FMR1-associated tremor/ataxia syndrome (FXTAS) C. FMR1-related primary ovarian insufficiency (POI) D. A and B E. B and C F. A, B, and C G. None of the above

E. B and C

A couple came to a genetics clinic for prenatal counseling when the wife was 10 weeks pregnant. She had 28/30 copies of the CGG repeat in the FMR1 gene. Subsequent testing found that the husband had 100 copies. Prenatal ultrasound showed that the fetus was a male. What diseases would the unborn daughter be at risk to have? A. Fragile X syndrome B. FMR1-associated tremor/ataxia syndrome (FXTAS) C. FMR1-related primary ovarian insufficiency (POI) D. A and B E. B and C F. A, B, and C G. None of the above

G. None of the above

A couple came to a genetics clinic for prenatal counseling when the wife was 10 weeks pregnant. She had 30/179 copies of the CGG repeat in the FMR1 gene. Subsequent testing found that the husband had 29 copies. Prenatal ultrasound showed that the fetus was a male. What diseases would the unborn son be at risk to have? A. Fragile X syndrome B. FMR1-associated tremor/ataxia syndrome (FXTAS) C. FMR1-related primary ovarian insufficiency (POI) D. A and B E. B and C F. A, B, and C G. None of the above

D. A and B

Boy with ID and macroorchidism and maternal uncle FHx.

***

Prenatal counseling and woman with 334-kb deletion in the FMR2 gene on Xq28. The microarray on the CVS showed that the fetus was a male with the maternal inherited deletion in the FMR2 gene. What disease would the unborn son be at increased risk to have? A. Fragile X syndrome B. FMR1-associated tremor/ataxia syndrome (FXTAS) C. FMR1-related primary ovarian insufficiency (POI) D. Mental retardation, X-linked, FRAXE type E. All of the above F. None of the above.

D. Mental retardation, X-linked, FRAXE type The FMR2 gene is located on Xq28, which lies approximately 150–600 kb distal to the FMR1 gene and is folate-sensitive. The FMR2 gene is associated with mental retardation, X-linked, FRAXE type, instead of fragile X syndrome Meng, Haiying. Self-assessment Questions for Clinical Molecular Genetics (p. 230). Academic Press. Kindle Edition.

Which one of the following disorders is NOT caused by loss-of-function changes? A. Fragile X syndrome B. Fragile X syndrome E C. Friedreich ataxia D. Huntington disease E. All of the above F. None of the above

D. Huntington disease

Which one of the following disorders is NOT caused by gain-of-function changes? A. Fragile X syndrome B. FMR1-associated tremor/ataxia syndrome (FXTAS) C. Huntington disease D. Myotonic dystrophy E. Spinocerebellar ataxia F. None of the above

A. Fragile X syndrome

Figure below shows Southern blot testing results using EcoR1 and EagI digestion and StB12.3 probe for the CGG repeat in the FMR1 gene. Numbers 7, 8, and 9 are the controls (7=premutation female; 8=full mutation female; and 9=normal female). Which one of the male patients in the figure has fragile X syndrome? A. 1 B. 2 C. 3 D. 4 E. 5 F. 6

A. 1 Fully methylated 2 - invalid signal pattern (not methylated) 4 - invalid signal pattern (pre-mutation should not be methylated) Full-mutation alleles usually have more than 200 CGG repeats with several hundred to several thousand repeats being typical and associated with aberrant hypermethylation of the FMR1 promoter in males and females. If the CGG repeat is in the normal to premutation range, the methylation is random in females. Males have only one copy of the X chromosome and the FMR1 gene usually is not methylated if the CGG repeat is in the normal to premutation range.

Figure below shows Southern blot testing results using EcoR1 and EagI digestion and StB12.3 probe for the CGG repeat in the FMR1 gene. Numbers 7, 8, and 9 are the controls (7=premutation female; 8=full mutation female; and 9=normal female). Which one of the male patients is at risk for FMR1-associated tremor/ataxia syndrome (FXTAS)? A. 1 B. 2 C. 3 D. 4 E. 5 F. 6

C. 3

Figure below shows Southern blot testing results using EcoR1 and EagI digestion and StB12.3 probe for the CGG repeat in the FMR1 gene. Numbers 7, 8, and 9 are the controls (7=premutation female; 8=full mutation female; and 9=normal female). Which one of the male patients is NOT at risk for Fragile X syndrome or FMR1-associated tremor/ataxia syndrome (FXTAS)? A. 1 B. 2 C. 3 D. 4 E. 5 F. 6

E. 5

Figure below shows Southern blot testing results using EcoR1 and EagI digestion and StB12.3 probe for the CGG repeat in the FMR1 gene. Numbers 1, 2, and 3 are the controls (1=premutation male; 2=full mutation male; and 3=normal male). Which one of the female patients is NOT at risk for Fragile X syndrome BUT is at risk for FMR1-associated tremor/ataxia syndrome (FXTAS) and premature ovarian failure? A. 4 B. 5 C. 6 D. 7 E. 8 F. 4 and 5 G. 4 and 6 H. 4, 5, and 6 I. 5 and 7 J. 4, 5, and 7 K. All of the above L. None of the above

H. 4, 5, and 6 4=premutation female (the premutation and normal alleles are methylated randomly); 5=premutation female (the premutation alleles are methylated due to skewed X inactivation); 6=premutation female (the normal allele is methylated due to skewed X inactivation);

Figure below shows Southern blot testing results using EcoR1 and EagI digestion and StB12.3 probe for the CGG repeat in the FMR1 gene. Numbers 1, 2, and 3 are the controls (1=premutation male; 2=full mutation male; and 3=normal male). Which one of the female patients has Fragile X syndrome ? A. 4 B. 5 C. 6 D. 7 E. 8 F. 4 and 5 G. 4 and 6 H. 4, 5, and 6 I. 5 and 7 J. 4, 5, and 7 K. All of the above L. None of the above

D. 7

Figure below shows Southern blot testing results using EcoR1 and EagI digestion and StB12.3 probe for the CGG repeat in the FMR1 gene. Numbers 1, 2, and 3 are the controls (1=premutation male; 2=full mutation male; and 3=normal male). Which one of the female patients does NOT have Fragile X syndrome and is NOT at risk for FMR-1associated tremor/ataxia syndrome (FXTAS) or premature ovarian failure ? A. 4 B. 5 C. 6 D. 7 E. 6 and 8 F. 4 and 5 G. All of the above H. None of the above

F. 4 and 5 4=premutation female (the premutation and normal alleles are methylated randomly); 5=premutation female (the premutation alleles are methylated due to skewed X inactivation);

Figure below shows triplet repeat–primed PCR of CGG repeats in FMR1 gene in a peripheral-blood sample. Which is the most appropriate interpretation? A. Normal female B. Normal male C. Female with a gray-zone mutation D. Male with a gray-zone mutation E. Female with a premutation F. Male with a premutation G. Female with a full mutation H. Male with a full mutation

B. Normal male

A. Normal female

E. Female with a premutation

H. Male with a full mutation

G. Female with a full mutation

Baby girl with ID and normal microarray and cytogenetics. Fragile X test showed she had approximately 250 copies of the CGG repeat for one allele. The baby girl was diagnosed with fragile X syndrome. As a follow-up, parental tests were ordered. The results showed that the mother has 29/32 copies of the CGG repeat, but the father has approximately 125 copies of the CGG repeat. Which one of the following would be the most appropriate explanation of the molecular results? A. The daughter inherited an expended permutation from the father. B. The father had gonadal mosaicism for a full mutation. C. The daughter inherited an expended normal allele from the mother. D. The mother had gonadal mosaicism for a full mutation. E. None of the above.

B. The father had gonadal mosaicism for a full mutation. To date, there have been no reports of male or female with normal alleles or carriers of intermediate alleles having offspring with an FMR1 allele in the full-mutation range. All fragile X males and the overwhelming majority of affected females inherited their mutations from their mother. Men with a premutation will almost always pass the premutation to all of their daughters. An extremely rare phenomenon involves unaffected males with a premutation who have had affected daughters, apparently by gonadal mosaicism for full mutations.

Which one of the following statements regarding the CGG repeat in the FMR1 gene for fragile X syndrome is CORRECT? A. Individuals, especially males, with repeats in the premutation range may expand to full mutation owing to somatic instability. B. Individuals, especially females, with repeats in the intermediate range may expand to full mutation owing to somatic instability. C. An FMR1 allele in the premutation range is unstable, and may expand to a full mutation through intergenerational transmission, especially through a carrier female. D. An FMR1 allele in the premutation range or full mutation range is usually methylated. E. If an individual has an allele that looks like a smear among the upper limit of the premutation range and low limit of full mutation range, the patient may be considered to have a premutation. F. None of the above.

C. An FMR1 allele in the premutation range is unstable, and may expand to a full mutation through intergenerational transmission, especially through a carrier female.

Which one of the following statements regarding the CGG repeat in the FMR1 gene for fragile X syndrome is CORRECT? A. A full mutation in males may shrink to premutation in daughters during transmission. B. Females with full mutation usually are not symptomatic. C. Fragile X–associated tremor/ataxia syndrome (FXTAS) only appears in male premutation carriers, but not females. D. Most of female premutation carriers develop premature ovarian failure (POI) before 40 years of age. E. A full mutation in females may shrink to premutation during transmission.

A. A full mutation in males may shrink to premutation in daughters during transmission.

Which one of the following statements regarding the CGG repeat in the FMR1 gene for fragile X syndrome is CORRECT? A. An FMR1 allele with a full mutation is hypertranscribed. B. An FMR1 allele with a premutation is transcriptionally silenced. C. Fragile X is more common in the Ashkenazi Jewish population than in Caucasians. D. The triplet-primed PCR may detect point mutations besides trinucleotide repeats. E. The normal allele may be methylated in a female premutation carrier.

C. Fragile X is more common in the Ashkenazi Jewish population than in Caucasians *corrected from D-- Evidence suggests that FXTAS results from the twofold to fivefold increased levels of the FMR1 mRNA in these patients. Triplet repeat–primed PCR (TP PCR) allows rapid detection of PCR products formed by a chimeric primer binding inside a triplet-repeat region. In TRP PCR for fragile X syndrome, one primer is anchored completely outside the CGG repeat region, whereas the other overlaps the CGG repeat and the adjacent nonrepeated sequence. A third primer can be anchored outside the CGG region that, when paired with the opposite anchored primer, will amplify “over” the CGG. Therefore, the triplet-primed PCR may detect copy-number changes of trinucleotide repeats, but not point mutations.

2 yo with combined PCR and Southern blot showing compound heterozygous 30/243 copies of the CGG repeats. Mother tested as 32/192. Brother1 with 172, brother 2 with 190 repeats, and sister with 29/192 repeats. Which one of the following individuals had highest risk of developing fragile X–associated tremor/ataxia syndrome (FXTAS)? A. Sister B. Brother 2 C. Mother D. Brother 1 E. Unpredictable

B. Brother 2

Combination PCR and Southern blot testing confirmed that the patient had compound heterozygous 30/243 copies of the CGG repeats in the FMR1 gene. Which one of the following describes the function of the FMR1 gene product? A. Protein kinase B. RNA-binding protein C. Structural protein D. Transmembrane protein E. Zinc-finger protein

B. RNA-binding protein associates with polyribosomes to suppress translation - cytoskeleton, synaptic transmission, neuronal migration

Molecular testing of the (CGG)n repeat in the FMR1 gene showed c.-129CGG(199) with the CVS sample when the gestational age was 10 weeks. Which one of following would most likely be the physician’s response to the results? A. Informing the couple that their unborn son carries a premutation allele and will be at risk for FXTAS. B. Informing the couple that their unborn son carries an abnormal allele and will have fragile X syndrome or FXTAS. C. Informing the couple that their unborn son carries an abnormal allele and that amniocentesis is recommended to establish the diagnosis. D. Informing the couple that their unborn child carries an abnormal allele and will have FXS. E. Informing the couple that their unborn child carries an abnormal allele and will have FXTAS and/or premature ovarian insufficiency (FXPOI).

C. Informing the couple that their unborn son carries an abnormal allele and that amniocentesis is recommended to establish the diagnosis. In this case, c.-129CGG(199) indicated that Southern blotting was used to characterize the CGG repeat in this chorionic villus sampling (CVS) sample and that the exact size of the repeat cannot be determined, which may be a premutation (55–200), or a full mutation (>200). Methylation would be helpful to determine whether the fetus had a premutation or a full mutation. Because methylation is not fully established at the time of CVS, follow-up amniocentesis would be appropriate to establish the diagnosis in this fetus

Which one of the following ranges for FMR1 clinical testing is acceptable? A. Consensus size ±6 repeats for alleles with <55 repeats B. Consensus size ±5 repeats for alleles with <55 repeats C. Consensus size ±4 repeats for alleles with <55 repeats D. Consensus size ±3 repeats for alleles with <55 repeats E. Consensus size ±2 repeats for alleles with <55 repeats F. Consensus size ±1 repeats for alleles with <55 repeats

B. Consensus size ±5 repeats for alleles with <55 repeats

The laboratory director put together a validation plan according to the ACMG guideline and grading criteria for CAP proficiency testing survey. Which one of the following ranges for FMR1 clinical testing is acceptable? A. Consensus size ±14 repeats for alleles with 56–100 repeats B. Consensus size ±12 repeats for alleles with 56–100 repeats C. Consensus size ±10 repeats for alleles with 56–100 repeats D. Consensus size ±8 repeats for alleles with 56–100 repeats E. Consensus size ±6 repeats for alleles with 56–100 repeats F. Consensus size ± 4 repeats for alleles with 56–100 repeats

C. Consensus size ±10 repeats for alleles with 56–100 repeats

The laboratory director put together a validation plan according to the ACMG guideline and grading criteria for CAP proficiency testing survey. Which one of the following ranges for FMR1 clinical testing is acceptable? A. Consensus size ±30 repeats for alleles with 56–100 repeats B. Consensus size ±20 repeats for alleles with 56–100 repeats C. Consensus size ±10 repeats for alleles with 56–100 repeats D. Consensus size ±1 SDs for alleles with >100 repeats E. Consensus size ±2 SDs for alleles with >100 repeats F. Consensus size ±3 SDs for alleles with >100 repeats

E. Consensus size ±2 SDs for alleles with >100 repeats

What gender bias exists for SCA1, SCA7, HD and FXS?

SCA1 = paternal anticipation SCA7 = maternal anticipation HD = paternal anticipation FXS = maternal anticipation

Disorders of Unstable Repeat Sequences Flashcards

(115 cards)