CLINICAL GENOMICS

MCQs FOR STUDENTS

1. A 28 year-old healthy female medical student, whose father had been diagnosed with Adult polycystic kidney disease (ADPKD), had ultrasound scan done on her two kidneys, which she inquisitively requested during a radiology posting and was normal. A week later she again requested for an MRI, and a T2 weighted breath-held MRI without contrast injection in one breath-hold and this revealed multiple tiny cysts (>10/kidney) in a cortical and perihilar distribution. DNA testing will most likely: A detect a truncating mutation in the PKD2 gene in her and her other affected family members. B detect contiguous deletion of PKD1/TSC2 with resultant end-stage renal disease. C detect a truncating mutation in the PKDH1 gene on chromosome 6p21 in her and her father. D detect a truncating mutation in the MCKD1 gene on chromosome 1q21, as the cause of her abnormality. E detect a truncating mutation in the PKD1 gene on chromosome 4q21 in her and her father

2. Which of the following is true concerning the pathogenesis of Adult polycystic kidney disease (ADPKD)? A ADPKD is characterized by numerous cysts within the renal calyceal system B Mutations of PKHD1 result in ADPKD, pancreatic cysts and hepatic biliary dysgenesis and fibrosis. C The cysts fluids originate in more than 98% of nephrons, and mostly derived from glomerular filtrate. D. defects in the gene product, polycystin-1 and polycystin-2, present in the cilia of tubular epithelia cells disrupt calcium signaling that normally inhibits renal tubule growth. E defects in the gene product, fibrocystin, found in the kidney, liver and pancreas, appears to be involved in the regulation of cell proliferation and adhesion

3. The process of DNA synthesis normally avoids transmitting errors to subsequent generations of cells. However, genetic abnormalities of DNA mismatch/repair do occur, and include all of the following, except: A B C D E ADPKD hereditary nonpolyposis colon cancer (HNPCC) ataxia telangiectasia Bloom syndrome xeroderma pigmentosum

4. Which of the following is the least common cause of end-stage renal disease? A B C D E Adult polycystic kidney disease Diabetes mellitus Hypertension They all cause ESRD with about the same frequency Unknown due to current lack of clinical data

5. Which of the following is not true concerning the anatomy of the gene?

A. A gene product can occasionally consist of RNA that is not translated. B. Exons refer to the portion of genes that are eventually spliced together to form mRNA. C. Introns refer to the spacing regions between the exons that are spliced out of precursor RNAs during RNA processing D. Gene transcription occurs when RNA polymerase begins to synthesize RNA from the DNA template. E. Mutations occur only in certain domains of a gene and point mutations that introduce a premature stop codon result in an amino acid substitution if the codon is altered.

6. A 25 years old, otherwise healthy male, has been selected as a potential kidney donor. The 55 years old father has a 10 years history of ADPKD with ESRD. Prior to the kidney transplant, a genetic counseling and direct mutation analysis for molecular diagnosis of ADPKD in the 25

years old kidney donor was scheduled to be performed. Which of the following facts about DNA sequencing is true except: A. It is completely an automated procedure, with the advantage of using a blood sample from the donor. B. The capillary electrophoresis-based Sanger method in which dideoxynucleotides are used to randomly terminate DNA polymerization at each of the four bases (A,G,T,C) is currently the most commonly used strategy. C. The use of fluorescently labeled dideoxynucleotides allows detection of the different bases and direct computer analysis of the DNA sequence. D. Newer DNA sequencing technologies, such as pyrosequencing chemistries; whole-genome sequencing using solid-phase sequencing; mass spectrometry and DNA chips are laborious less cost-effective E. The major limitation of direct DNA testing is that definitive disease-associated mutationd are found in only about 40 60% of case.

7. All the following information concerning the anatomy of locus, alleles and a gene, are true, except: A. The particular allele which causes the characteristic of an individual to be expressed in a normal fashion is often referred to as the wild-type allele. B. If a male inherits a recessive mutant allele such as color blindness on his X chromosome, he expresses color blindness because he possesses the wild-type allele on his Y chromosome. C. There are two chromosomes of each kind and hence two alleles of each kind of gene, except for the sex chromosomes, which is said to be hemizygous for alleles carried on the males X chromosome. D. An allele is any one of two or more alternative forms of a gene that occupies a fixed position in the chromosome. E. A locus is the specific position of a particular gene or one of its alleles, in all homologous chromosomes.

8. Technical advances in DNA sequencing and computational bioinformatics have led to the completion of the DNA sequence for the human chromosomes. Which of the following is true concerning the Human Genome Project (HGP) and its current developments?

A. The whole genomes of other organisms are yet to be sequenced completely. B. HGP is yet to commence comparative genomics. C. Studies of large-scale expression of RNAs (functional genomics) and proteins (proteomics) can detect differences between various tissues in health and disease. D. Effort to examine ethical and legal implications of the HGP has not yet been initiated. E. HGP is yet to identify genes that play critical roles in the development of polygenic and multifactorial disorders.

9. Which of the following statements are NOT TRUE concerning mutations and the transmission of genetic diseases:

A. It is a change in the primary nucleotide sequence of DNA regardless of its functional consequences and can occur in the germline (sperm or oocytes) during embryogenesis or in somatic tissues. B. Somatic mutations are associated with neoplasia because they confer a growth advantage to cells. C. Epigenetic events are heritable changes that do not involve changes in gene sequence (e.g., altered DNA methylation), therefore, do not influence gene expression or genetic damage. D. Mutations are usually stable, with the exception of triplet nucleotide repeats. E. If a purine is replaced by another purine base (A G), the substitution is called a transitions; on the other hand if a purine is replaced by pyrimidine it is referred to as transversions.

10. A newly wedded couple comes in to your clinic after their honeymoon and states that they are planning to have a child soon. The man is 60 years old and the woman is 34 years old. The man gave a family history of achondrodysplasia, while the woman gave a family history of neurofibromatosis. They were both concerned about the risk of transmitting any genetic disease to their child and came in for genetic counseling and your most likely response would include all of the following EXCEPT: A. Mutation rates are difficult to determine in humans because many mutations are silent and because testing is often not adequate to detect the phenotypic consequences. B. The probability of acquiring new point mutations is much greater in the female germline than the male germline, in which rates of aneuploidy are increased. C. The incidence of achondrodysplasia, Marfan syndrome and neurofibromatosis as a result of new point mutations in spermatogonia increases with paternal age D. It is estimated that about 1 in 10 sperm carries a new deleterious mutation. E. The rates for new mutations are calculated for autosomal dominant and X-linked disorders and are ~105106/locus per generation and therefore new mutation can be transmitted to the

affected individual but does not necessarily imply that the parents are at risk to transmit the disease to other children.

MATCHING: PART A A. Prader-Willi syndrome (neonatal hypotonia, developmental delay, obesity, short stature, and hypogonadism) B. Marfan syndrome C. Huntington disease D. Single nucleotide polymorphisms (SNPs) E. ADPKD caused by PKD2 gene mutation F. Fragile X syndrome G. Promyelocytic leukemia.

1. Regulation of gene expression is influenced by epigenetic events, such as genetic imprinting, which is a processes in which DNA methylation or histone modifications is associated with gene silencing. 2. This class of mutation consists of deletions or insertions that shift the reading frame of the message 3. This class of mutation consists of trinucleotide repeats repeats that encodes FMR-1 protein. 4. The t(15;17) chromosomal translocation fuses the PML gene to a portion of the retinoic acid receptor (RAR ) gene. 5. An autosomal dominant disorder caused by expansion of a CAG trinucleotide repeat that encodes a polyglutamine tract. 6. Characterization, using DNA chips, provides important tool for comprehensive analyses of genetic variation, which may be useful pharmacogenomics and prediction of disease predilection. 7. Angiotensin II receptor blockers may slow disease progression, as demonstrated by the human genome Project.

MATCHING: PART B

A. B. C. D. E. F. G. H. I. J.

Frameshift mutation Missense mutation synonymous polymorphism point mutations Gene conversion non synonymous polymorphism Nonsense mutation Gain-of-function mutations Inactivating mutations Haploinsufficiency

1. Mutations involving single nucleotides 2. DNA sequence change that occurs in a coding region and thereby alters an amino acid sequence 3. DNA sequence variations that do not result in a perceptible phenotype and consist of single basepair substitutions that do not alter the protein coding sequence because of the degenerate nature of the genetic code 4. Small nucleotide deletions or insertions that cause a shift of the codon reading frame 5. Sequence variations that alter mRNA stability, translation, or amino acid sequence, but do not result in a perceptible phenotype. 6. Reading frame alterations that result in an abnormal protein segment of variable length before termination of translation occurs at a stop codon 7. Nonreciprocal exchange of homologous genetic information, used to explain how an internal portion of a gene is replaced by a homologous segment copied from another allele or locus. 8. Mutation in a single allele in and which one normal allele is not capable of maintaining a normal phenotype, seen in Von HippelLindau syndrome and other diseases associated with mutations in transcription factors. 9. Mutation is typically dominant, and results in phenotypic alterations when a single allele is affected. 10. Mutation is typically recessive, and the affected individual is either homozygous or compound heterozygous for the disease-causing mutations.

ANSWERS
#1, ANSWER=A: A detect a truncating mutation in the PKD2 gene in her and her other affected family members. B detect contiguous deletion of PKD1/TSC2 with resultant end-stage renal disease: this is seen in tuberous sclerosis. C detect a truncating mutation in the PKDH1 gene on chromosome 6p21 in her and her father: this is seen in ARPKD . D detect a truncating mutation in the MCKD1 gene on chromosome 1q21, as the cause of her abnormality: this is seen in medullary cystic kidney disease. detect a truncating mutation in the PKD1 gene on chromosome 4q21 in her and her father: a E mutation in the PKD1 gene is seen on chromosome 16p.

2.

Which of the following is true concerning the pathogenesis of Adult polycystic kidney disease (ADPKD)?

ANSWER= D A ADPKD is characterized by numerous cysts within the renal calyceal system. INCORRECT: ADPKD is characterized by cysts within the renal parenchyma. Both ADPKD and ARPKD lack cysts within the renal calyceal system. B Mutations of PKHD1 result in ADPKD, pancreatic cysts and hepatic biliary dysgenesis and fibrosis. INCORRECT: Mutations of PKHD1 result in ARPKD, pancreatic cysts and hepatic biliary dysgenesis and fibrosis. C The cysts fluids originate in more than 98% of nephrons, and mostly derived from glomerular filtrate. INCORRECT: The cysts fluids originate in about 2% of nephrons, and initially derived from glomerular filtrate, but mostly derived from transepithelia movement.

D. CORRECT: defects in the gene product, polycystin-1 and polycystin-2, present in the cilia of tubular epithelia cells disrupt calcium signaling that normally inhibits renal tubule growth. E defects in the gene product, fibrocystin, found in the kidney, liver and pancreas, appears to be involved in the regulation of cell proliferation and adhesion. INCORRECT: defects in the gene product, fibrocystin, found in the kidney, liver and pancreas, appears to be involved in the regulation of cell proliferation and adhesion in ARPKD.

3. The process of DNA synthesis normally avoids transmitting errors to subsequent generations of cells. However, genetic abnormalities of DNA mismatch/repair do occur, and include all of the following, except: ANSWER: A A B C D E ADPKD hereditary nonpolyposis colon cancer (HNPCC) ataxia telangiectasia Bloom syndrome xeroderma pigmentosum

4. Which of the following is the least common cause of end-stage renal disease? ANSWER: A A B C D E 5. Adult polycystic kidney disease Diabetes mellitus Hypertension They all cause ESRD with about the same frequency Unknown due to current lack of clinical data Which of the following is not true concerning the anatomy of the gene?

ANSWER: E. Mutations occur in all domains of a gene and point mutations that introduce a premature stop codon result no amino acid formation.

A. A gene product can occasionally consist of RNA that is not translated. B. Exons refer to the portion of genes that are eventually spliced together to form mRNA. C. Introns refer to the spacing regions between the exons that are spliced out of precursor RNAs during RNA processing D. Gene transcription occurs when RNA polymerase begins to synthesize RNA from the DNA template. E. Mutations occur only in certain domains of a gene and point mutations that introduce a premature stop codon result in an amino acid substitution if the codon is altered.

6.

The following facts about DNA sequencing is true except:

ANSWER: D Newer DNA sequencing technologies, such as pyrosequencing chemistries; wholegenome sequencing using solid-phase sequencing; mass spectrometry and DNA chips are faster and more cost-effective. A. It is completely an automated procedure. B. The capillary electrophoresis-based Sanger method in which dideoxynucleotides are used to randomly terminate DNA polymerization at each of the four bases (A,G,T,C) is currently the most commonly used strategy. C. The use of fluorescently labeled dideoxynucleotides allows detection of the different bases and direct computer analysis of the DNA sequence. D. Newer DNA sequencing technologies, such as pyrosequencing chemistries; whole-genome sequencing using solid-phase sequencing; mass spectrometry and DNA chips are laborious less cost-effective E. It is possible to deduce the DNA sequence by examining the progression of fragment lengths generated in each of the four nucleotide reactions, after separating the array of terminated DNA fragments using high-resolution gel or capillary electrophoresis.

7. All the following information concerning the anatomy of locus, alleles and a gene, are true, except: ANSWER = B A. The particular allele which causes the characteristic of an individual to be expressed in a normal fashion is often referred to as the wild-type allele. B. If a male inherits a recessive mutant allele such as color blindness on his X chromosome, he expresses color blindness because he possesses the wild-type allele on his Y chromosome: If a male inherits a recessive mutant allele such as color blindness on his X chromosome, he expresses color blindness because he lacks the wild-type allele on his Y chromosome. C. There are two chromosomes of each kind and hence two alleles of each kind of gene, except for the sex chromosomes, which is said to be hemizygous for alleles carried on the males X chromosome. D. An allele is any one of two or more alternative forms of a gene that occupies a fixed position in the chromosome. E. A locus is the specific position of a particular gene or one of its alleles, in all homologous chromosomes.

Technical advances in DNA sequencing and computational bioinformatics have led to the completion of the DNA sequence for the human chromosomes. Which of the following is true concerning the Human Genome Project (HGP) and its current developments?
8.

ANSWER = C

A. In addition to the human genome, the whole genomes of some organisms have been sequenced partially or completely. B. There have been advancements in comparative genomics

C. There have been advancements in study of large-scale expression of RNAs (functional genomics) and proteins (proteomics) in order to detect differences between various tissues in health and disease. D. Effort to examine ethical and legal implications of the HGP have been initiated

E. HGP has helped in the identification of genes that play critical roles in the development of polygenic and multifactorial disorders.

Which of the following statements are NOT TRUE concerning mutations and the transmission of genetic diseases: ANSWER: C

9.

A. It is a change in the primary nucleotide sequence of DNA regardless of its functional consequences and can occur in the germline (sperm or oocytes) during embryogenesis or in somatic tissues. B. Somatic mutations are associated with neoplasia because they confer a growth advantage to cells. C. Epigenetic events are heritable changes that do not involve changes in gene sequence (e.g., altered DNA methylation), therefore, do not influence gene expression or genetic damage: ANSWER: C Epigenetic events are heritable changes that do not involve changes in gene sequence (e.g., altered DNA methylation), and it may influence gene expression or genetic damage.

D. Mutations are usually stable, with the exception of triplet nucleotide repeats. If a purine is replaced by another purine base (A G), the substitution is called a transitions; on the other hand if a purine is replaced by pyrimidine it is referred to as transversion

10. A newly wedded couple come in to your clinic after their honeymoon and states that they are planning to have a child soon. The man is 60 years old and the woman is 34 years old. The man gave a family history of achondrodysplasia, while the woman gave a family history of neurofibromatosis. They were both concerned about the risk of transmitting any genetic disease to their child and came in for genetic counseling and your most likely response would include all of the following EXCEPT: ANSWER: B A. Mutation rates are difficult to determine in humans because many mutations are silent and because testing is often not adequate to detect the phenotypic consequences. B. The probability of acquiring new point mutations is much greater in the female germline than the male germline, in which rates of aneuploidy are increased: ANSWER B: The probability of acquiring new point mutations is much greater in the male germline than the female germline, in which rates of aneuploidy are increased.

C. The incidence of achondrodysplasia, Marfan syndrome and neurofibromatosis as a result of new point mutations in spermatogonia increases with paternal age D. It is estimated that about 1 in 10 sperm carries a new deleterious mutation. E. The rates for new mutations are calculated for autosomal dominant and X-linked disorders and are ~105106/locus per generation and therefore new mutation can be transmitted to the affected individual but does not necessarily imply that the parents are at risk to transmit the disease to other children.

MATCHING: PART A_ ANSWERS A. Prader-Willi syndrome (neonatal hypotonia, developmental delay, obesity, short stature, and hypogonadism) B. Marfan syndrome

C. D. E. F. G.

Huntington disease Single nucleotide polymorphisms (SNPs) ADPKD caused by PKD2 gene mutation Fragile X syndrome Promyelocytic leukemia.

1. A. Regulation of gene expression is influenced by epigenetic events, such as genetic imprinting, which is a processes in which DNA methylation or histone modifications is associated with gene silencing. 2. E. This class of mutation consists of deletions or insertions that shift the reading frame of the message 3. F. This class of mutation consists of CGG trinucleotide repeats that encodes FMR-1 protein. 4. G. The t(15;17) chromosomal translocation fuses the PML gene to a portion of the retinoic acid receptor (RAR ) gene.. 5. C. An autosomal dominant disorder caused by expansion of a CAG trinucleotide repeat that encodes a polyglutamine tract. 6. D. Characterization, using DNA chips, provides important tool for comprehensive analyses of genetic variation, which may be useful pharmacogenomics and prediction of disease predilection. 7. B. Angiotensin II receptor blockers may slow disease progression, as demonstrated by the human genome Project.

MATCHING: PART B_ ANSWERS

A. B. C. D. E. F.

Frameshift mutation Missense mutation synonymous polymorphism point mutations Gene conversion non synonymous polymorphism

G. H. I. J.

Nonsense mutation Gain-of-function mutations Inactivating mutations Haploinsufficiency

1. D. Mutations involving single nucleotides 2. B. DNA sequence change that occurs in a coding region and thereby alters an amino acid sequence 3. C. DNA sequence variations that do not result in a perceptible phenotype and consist of single base-pair substitutions that do not alter the protein coding sequence because of the degenerate nature of the genetic code 4. A. Small nucleotide deletions or insertions that cause a shift of the codon reading frame 5. F. Sequence variations that alter mRNA stability, translation, or amino acid sequence, but do not result in a perceptible phenotype. 6. G. Reading frame alterations that result in an abnormal protein segment of variable length before termination of translation occurs at a stop codon 7. E. nonreciprocal exchange of homologous genetic information, used to explain how an internal portion of a gene is replaced by a homologous segment copied from another allele or locus. 8. J. Mutation in a single allele and in which one normal allele is not capable of maintaining a normal phenotype, seen in Von HippelLindau syndrome and other diseases associated with mutations in transcription factors. 9. H. Mutation is typically dominant, and results in phenotypic alterations when a single allele is affected. 10. I. Mutation is typically recessive, and the affected individual is either homozygous or compound heterozygous for the disease-causing mutations.