(Adapted from http://www.med.umich.edu/lrc/coursepages/M1/humangenetics/genetics/subjectqs.html)

Formative Evaluation I (Embryology and Genetics 2010)

1. A disorder causing muscle weakness and epilepsy afflicts several members of the pedigree below. What is the MOST LIKELY mode of inheritance?

A non-genetic; environmental causes are most likely B X-linked recessive C autosomal recessive D mitochodrial (maternal inheritance) E autosomal dominant

2. A young woman of northern European descent is the single parent of a child with autosomal recessive cystic fibrosis. She marries her first cousin and becomes pregnant. What is the probability that her child will have cystic fibrosis?

A 1/2500 B 1/100 C 1/32 D 1/8 E 1/4

3. The family below is segregating the mutant allele for disease X, a very rare genetic disorder inherited in an autosomal recessive pattern, with 100% penetrance. II-2's first wife delivers an affected child, but dies in childbirth. II-2 later marries his first wife's half-sister (II-3), and she becomes pregnant. What is the chance that this child will be affected?

A 1/2 B 1/4 C 5/32 D 1/16 E mutant allele frequency, squared (q2)

4. Choose one of the following terms that best matches each clinical vignette. Each term may be used once, more than once, or not at all. A. Variable expressivity B. Anticipation C. Incomplete penetrance D. Allelic heterogeneity E. Locus heterogeneity

A 24-year-old woman with myotonic dystrophy has significant muscle weakness and wasting. She has a one-year-old son with very poor muscle tone and severe weakness and significant developmental delay. Her affected 55-year-old father has cataracts but no muscle weakness.

A B C D E

A man and a woman, each of whom has autosomal recessive congenital deafness, have four biological children, each of whom has normal hearing.

A B C D E

A 40-year-old man with neurofibromatosis (NF1) has a plexiform neurofibroma of his leg that has caused significant disfigurement, and hundreds of cutaneous neurofibromas. His 43-year-old sister has cafe-au-lait spots and Lisch nodules of the iris, but no neurofibromas. His 19-year-old son has cafe-au-lait spots, a dozen cutaneous neurofibromas, and scoliosis (curvature of the spine).

A B C D E

Molecular analysis of the ornithine transcarbamylase (OTC) gene is carried out on two unrelated boys with X-linked OTC deficiency. One is found to have a large deletion in the 5' end of the gene; the other has a missense mutation in an exon toward the 3' end of the gene.

A B C D E

5. The family below is segregating a very rare autosomal recessive disease with 100% penetrance. The disease is present and recognizable at birth and does not decrease fitness. Assume no locus heterogeneity. What is the chance that the fetus (IV-1) is affected with this disease?

A 1/4 B 1/2 C 1/9 D 2/9 E 4/9

6. Below is a portion of a large pedigree segregating for a particular coagulation disorder. What mode of inheritance is demonstrated?

A autosomal dominant B X-linked dominant C mitochondrial inheritance D autosomal recessive E X-linked recessive

7. Hemophilia A and hemophilia B have nearly identical phenotypes, but they result from mutations in different genes on the X chromosome. This is an example of:

A Double heterozygosity B Compound heterozygosity C Locus heterogeneity D Allelic heterogeneity E Variable expressivity

8. What is the most likely pattern of inheritance in this pedigree?

A Mitochondrial B X-linked dominant C Autosomal dominant D Autosomal recessive E X-linked recessive

9. What is the most likely pattern of inheritance in this pedigree?

A Autosomal recessive B X-linked dominant C Autosomal dominant D X-linked recessive E Mitochondrial

10. Myotonic dystrophy may show increasing severity and earlier age of onset in successive generations. This phenomenon is known as:

A Variable expressivity B Locus heterogeneity C Compound heterozygosity D Incomplete penetrance E Anticipation

11. The pedigree below is from a family with cystic fibrosis, an autosomal recessive condition. What is the best estimate that individual I-3 is a carrier of cystic fibrosis?

A 1/4 B 1/3 C 1/2 D 2/3 E 3/4

12.Sickle cell anemia is:

A caused by mutations in either the alpha-globin gene or the beta-globin gene.

B rarely due to the same mutation in unrelated individuals.

C always caused by the same point mutation in the beta-globin gene.

D an autosomal dominant disease.Ean X-linked recessive disease.

13.The "triplet repeat" in Huntington Disease refers to: A An amino acid repeat consisting of: C-A-G B A nucleic acid repeat consisting of: G-A-T C An amino acid repeat consisting of: Gly-X-YD A nucleic acid repeat consisting of: C-A-G E A nucleic acid repeat consisting of: T-A-G

14. RNA contains the base adenine (A) in place of guanine (G).

A True B False

15. The DNA shown below is from the 3' end of the -globin gene, which is mutated in sickle cell anemia (autosomal recessive). Which bands would be seen in a Southern blot of DNA from normal subjects digested with EcoRI and hybridized with Probe A?

A 4 kb band, 6 kb band, and 10 kb band

B 6 kb band only

C 6 kb band and 10 kb band

D 4 kb band and 10 kb band

E 4 kb band only

16. A particular RFLP is diagrammed below. 'E' represents invariant EcoRI restriction sites. '*' represents polymorphic EcoRI sites. The dark box represents the location of a particular DNA probe 'A'. What are all the possible alleles (i.e. size of bands) seen on a Southern blot probed with 'A'?

A 1kb, 2kb, 3kb, 4kb, 5kb, 6kb

B 1kb, 3kb, 4kb, 6kb

C 3kb, 4kb, 6kb

D 2kb, 3kb, 6kb

E None of the above

17. The "triplet repeat" in Huntington Disease refers to:

A A nucleic acid repeat consisting of: C-A-G

B A nucleic acid repeat consisting of: G-A-T

C An amino acid repeat consisting of: C-A-G

D An amino acid repeat consisting of: Gly-X-Y

E A nucleic acid repeat consisting of: T-A-G

18. True or False: If disease X is linked to marker locus Y, then there must be an association between disease X and a particular allele of marker locus Y.

A True B False

19. The G8 RFLP marker is closely linked to the Huntington disease (HD) locus, and it is useful for linkage analysis in HD families.

True or False: The base changes responsible for the G8 polymorphism are also responsible for HD.

A True B False

20. The concept that genetic counseling must be nondirective arises directly from respect for which of the following principles of medical ethics?

A Justice

B Paternalism

C Autonomy

D Beneficence

E None of the above

21. Confidentially in the physician-patient relationship should be broken in which of the following clinical scenarios?

A A young woman has just tested positive for HIV. She begs you not to tell the test result to her boyfriend of 4 years.

B Your 23 year-old patient is starting a new job and her employer requests the results of her genetic test for expansion of triplet repeats in the Huntington Disease gene.

C You see a patient in the psychiatry outpatient clinic who tells you he has recurring thoughts of murdering his wife, and he is now devising a realistic plan to do so.

D All of the above

E A and C only

22. Below is a family with a normal son, and a daughter with trisomy 13. DNA samples from all four individuals were analyzed for an RFLP on chromosome 13. The results are shown below the pedigree. This RFLP has alleles of 10kb, 8kb, 6kb, and 4kb. Note that the 6kb band on the daughter (II-2) and the 4kb band on the mother (I-2) are of double intensity. Based on these data, in which meiotic division did the non-disjunction event occur?

A Paternal meiosis I B Paternal meiosis II C Maternal meiosis I D Maternal meiosis II E Maternal meiosis I or maternal meiosis II

23. Prader-Willi syndrome (PWS) can result from either an interstitial deletion involving the paternal copy of chromosome subregion 15q1-q13 or from maternal uniparental disomy of chromosome 15. The reason for this is: A The maternal copy of the gene(s) responsible for PWS is imprinted and is not expressed. B The maternal copy of the gene(s) responsible for Angelman syndrome (AS) is imprinted and

is not expressed. C PWS results from an anomaly of X-chromosome inactivation. D The maternal copy of the gene(s) responsible for PWS exerts a dominant negative effect of

the paternal allele. E The paternal copy of the gene(s) responsible for PWS is imprinted and is not expressed.

24. All of the following karyotypes are found in spontaneous abortuses. Which of the following is least likely to be found in a live-born infant? A 46, XY B 45, X C 47, XX, +21 D 47, XX, +16 E 69, XXX

25. In which of the following phenotypic females does a testis develop? A 46, XY with an interstitial deletion of Yp involving the SRY gene B 46, XX C 45, X D 46, XY with a point mutation in the HMG domain of the SRY gene E 46, XY with X-linked androgen receptor deficiency

26. Below is a pedigree of a family with Fragile X Mental Retardation (FMR). Filled symbols represent individuals with mental retardation. Which of the following individuals has the greatest risk of also being affected?

A III-1 B III-2 C III-3 D IV-2

27. A phenotypically normal woman with a 45, XX, -14, -21, +t(14q,21q) karyotype has a karyotypically normal husband. Among their liveborn offsping, which of the following is LEAST likely? A 46, XX B 46, XY, -14, +t(14q,21q) C 46, XY, -21, +t(14q,21q) D 45, XY, -14, -21, +t(14q,21q) E 45, XX, -14, -21, +t(14q,21q)

28. A karyotypically normal couple has a child with trisomy 21 Down syndrome. DNA analysis if 21q polymorphic markers reveals the following results. (Letters refer to polymorphic loci; numbers refer to alleles at that locus.) In which meiotic division did nondisjunction occur?

Marker Locus Father Mother child A 1, 2 2, 2 1, 2, 2 B 1, 1 2, 2 1, 2, 2 C 1, 1 1, 1 1, 1, 1 D 1, 1 1, 2 1, 2, 2

A Maternal meiosis I B Maternal meiosis II C Paternal meiosis I D Paternal meiosis II E Paternal meiosis I or II

29. A chromosomal analysis is obtained on a young woman with mild signs of Turner syndrome and reveals a 46,XX/45,X karyotype. Nondisjunction is most likely to have occurred in: A maternal meiosis I B maternal meiosis II C paternal meiosis I D paternal meiosis II E mitosis after fertilization

30. Which of the following human diseases is least likely to be caused by aneuploidy? A Down syndrome B Turner syndrome C Fragile X syndrome D Klinefelter syndrome

31. Fragile X syndrome (FraX) is an X-linked disease characterized by moderate to severe mental retardation. The molecular basis for this disease is expansion of a CGG triplet repeat in the first exon of the FMR-1 gene on the long arm of the X-chromosome. Normal individuals generally have 6-52 repeats with a mode of 30; affected individuals have >230 repeats. In the pedigree, filled symbols represent mentally retarded individuals. The number of CGG repeats is shown below the symbols for individuals in generations I and II. What is the probability that III-4 will be retarded because of FraX?

A

34. Ankylosing spondylitis is a chronic inflammatory arthritis affecting the spine and sacroiliac joints. 95% of Caucasian patients are positive for the HLA-B27 haplotype; whereas, 7% of all Caucasians are positive. This is evidence for: A Linkage of ankylosing spondylitis to the HLA-B locus. B Association of ankylosing spondylitis with the B27 allele of the HLA-B locus. C Neither.

35. The heterozygote carrier frequency (2pq) for an X-linked recessive disease with a disease frequency of 1/10,000 is greater than the heterozygote carrier frequency for an autosomal recessive disease with a disease frequency of 1/1,000,000. A True B False

36. If 1 out of every 250,000 people have Disease X, a nonlethal autosomal recessive disorder, what is the approximate carrier frequency of this disease? (Assume Hardy-Weinberg equilibrium.) A 1/1000 B 1/500 C 1/250 D 1/50 E 1/25

37. The average recurrence risk for a couple that has had a child with cleft lip, a multifactorial birth defect, is approximately 4%. What is the recurrence risk if the couple has two affected children? A 2% B 4% C 10% D 25% E 50%

38. Which statement is a prediction of the multifactorial threshold model? A The differential risk to relatives of an affected proband increases as the disease prevalence

decreases. B Affected individuals almost always have an affected parent. C An individual's risk is not altered by the number of affected first-degree relatives. D The age of onset decreases when there are affected relatives in two previous generations.

39. Which of the following observations is the strongest evidence for an important genetic component in the causation of type-1 diabetes mellitus (IDDM)? A Pancreatic B-cell autoantibodies are frequently present. B Approximately 10% of affected indivifuals have an affected sibling. C Onset of disease is usually in childhood. D The concordance rate in monozygotic twins is approximately 30%. E The concordance rate in monozygotic twins is five times that in dizygotic twins. 40. The family below is segregating an autosomal form of Ehlers-Danlos syndrome. Shaded individuals are affected with the disorder. You type each of the family members for a polymorphic DNA linked marker, with results shown below each individual (A-D represent individual alleles for the DNA marker).

The disease in this family is linked to which allele of the marker? A A B B C C D D 41. Assume only one recombination event has occurred in this family between the marker locus and the disease gene mutation. Which individual's marker genotype demonstrates that the recombination has occurred? A I-1 B II-2 C III-3 D III-4 E III-5

42. Familial retinoblastoma (FRB) is an autosomal dominant cancer predisposition syndrome, due to a defect in the RB tumor suppressor gene. An affected individual typically inherits a single defective copy from one parent, and a normal copy from the other parent. Below are Southern blots for an individual with FRB; both normal and tumor cells were typed for three RFLP markers flanking the RB locus on chromosome 13 (N = normal cells, T = tumor cells). Based upon these data, which of the following is the most likely explanation for the loss of heterozygosity in this individual? A Loss of the normal chromosome 13 B Independent second mutation C Mitotic crossover D Loss of the normal chromosome 13 and reduplication of the mutant chromosome 13

43. Each of the following have been observed as mechanisms resulting in the activation of a proto-oncogene except: A a chromosome translocation fusing portions of the oncogene and another cellular gene B inactivation of an oncogene by telomerase activity C a point mutation altering the function of the oncogene protein product D Capture of the oncogene sequence by a retrovirus E amplification of an oncogene as small, sub-chromosomal fragments (double minutes) 44. All of the following provide supporting evidence for the clonal origin of a tumor EXCEPT: A All cells from the tumor carry the same abnormal chromosome. B The tumor is from a female heterozygous for a G6PD polymorphism. All of the cells from the

tumor express the same G6PD allele. C In a person heterozygous for a particular DNA polymorphism, all tumor cells show reduction to

homozygosity for the same marker allele. D All cells from the tumor carry an identical rearrangement of the immunoglobin gene cluster.

E All cells from the tumor carry exactly 46 chromosomes. 45. Patients with familial retinoblastoma carry a germline mutation in one copy of the Rb gene. Potential mechanisms for inactivation of the other allele in a retinoblastoma tumor arising in one of these patients include: A Mitotic crossing over B loss of the normal chromosome 13 C an independent point mutation D all of the above E none of the above F A & C 46. The functions which have been identified for the proteins expressed by cellular proto-oncogenes include all of the following except: A enzyme involved in DNA mismatch repair B growth factor receptor C component of a signal transduction pathway D growth factor E transcription factor 47. Which of the following clinical features are characteristic of familial cancer syndromes?A Observed tumor types are rarely seen as sporadic cancers B Earlier mean age of cancer onset, compared to sporadic form of the same tumor type C Two or more independent primary tumors in a single individual D all of the above E none of the above F A & B 48. Which is NOT a typical mechanism by which a proto-oncogene is converted to an oncogene?A Complete deletion of the proto-oncogene B Amplification of the proto-oncogene C A chromosomal translocation resulting in the up-regulation of the proto-oncogene D A point mutation in the proto-oncogene

49. The transforming oncogene of the Simian Sarcoma Virus (SSV) is the sis gene. You perform a Southern blot on your own DNA, using the sis gene as a probe, and find several hybridizing bands.

True or False: This result demonstrates chronic infection of your blood cells with the SSV virus.

A True B False 50. Consider an autosomal recessive disease with an incidence of 1/10,000 in the general population (assume 100,000 people in Ann Arbor). Your best friend comes to you very upset--he has just taken a screening test for this disease and gotten a positive result. He is convinced he is a carrier, despite having no family history of the disease. You try to reassure him, but he says, "Don't bother. The Clinic said this test has 98% sensitivity and 90% specificity. With that level of sensitivity, it must be correct!" What is the chance your friend is NOT a carrier? A 2% B 10% C 17% D 49% E 83% 51. A couple in their 30's who have two healthy children now have a pregnancy that results in the birth of a stillborn girl with multiple congenital anomalies. Which of the following would be least appropriate to talk to the couple about shortly after their daughter's birth? A Available genetic counseling and social services. B Options regarding funeral, memorial, and/or burial services. C Further evaluation of the infant (including physical examination, autopsy, and genetic testing)

to determine the etiology of the infant's problems. D Opportunities to see, spend time with, and hold their stillborn infant. E Recommendation for the mother to have an immediate tubal ligation (sterilization procedure)

during this hospitalization to avoid a recurrence of the same problem, especially given they already have two healthy children.

52. A child is born with a cleft lip and palate. This birth defect may be associated with the following: A A disruption defect related to amniotic bands. B A healthy, otherwise completely normal, newborn infant. C A chromosome disorder such as trisomy 13. D All of the above. E Only A and C above. 53. Which is true of newborn screening tests for genetic diseases? Newborns are typically screened for genetic diseases: A which are treatable and/or preventable. B which are fatal by one year of age. C when a first or second degree relative is known to be affected. D which are irreversible or untreatable disorders. E Newborns are screened for all known genetic diseases. 54. A 26-year-old woman of Norwegian descent seeks genetic counseling. Her brother died at age eight of documented cystic fibrosis. Both of their parents are deceased. The woman undergoes DNA testing for 70 CF mutations which collectively detects approximately 90% of CF carriers of northern European descent. Testing reveals that she is negative for all 70 mutations. What is the probability that she is a heterozygous carrier of CF? A 2/3 B 1/6 C 1/15 D 1/25 E < 1%

55. A 26-year-old male medical student who has no neurological or psychiatric problems undergoes genetic testing to determine if he has a mutation in his Huntington Disease (HD) gene. Several of his maternal relatives, including his mother, have well documented HD.

His test results are: HD allele 1: 17 repeatsHD allele 2: 43 repeats

The most accurate interpretation of this test is: A He is an asymptomatic individual who inherited an HD gene mutation and will develop

symptoms of the disease if he lives long enough. B Luckily, he has one normal allele. Therefore he is only a gene carrier and will never develop

the disease. C These test results are inconclusive and therefore his 50/50 risk of inheriting the disease from

his mother has not been modified by the test. D He has HD and should seriously consider another occupation as he will never be able to

practice medicine competently. E He has inherited one HD gene mutation, but given that he currently has no symptoms by the

age of 26, it is most likely that he will never develop the disease. 56. The family below is segregating an X-linked recessive disorder with 100% penetrance. Shaded individuals are affected with the disorder. What is the chance that the woman's next child (IV-5) is an affected son?

A 1/4 B 1/8 C 1/9 D 1/18 E 1/36

57. A woman has a brother affected with a rare autosomal recessive disorder (she herself is not affected). This disorder is 100% penetrant at birth. She undergoes a carrier screening test which detects carriers with 98% sensitivity, and 5% false positive rate; she tests positive. Which of the following is the best estimate of her risk for being a carrier? A 100% B 97.5% C 66.7% D 50% E 33.3% 58. The family below is segregating a mutation for Duchenne Muscular Dystrophy (DMD), a lethal X-linked recessive disorder. Filled symbols represent individuals affected with DMD. Individual III-1, 5 y.o., has muscle weakness and wasting, and has an abnormal muscle biopsy. Both III-1, and her sister III-2, aged 1 y.o., have normal karyotypes. What is the risk that III-2 is a carrier for DMD?

A 0% B 25% C 50% D 75% E 100%

59. True or False: Presymptomatic diagnosis for Huntington's disease requires DNA analysis of at least one affected relative. A True B False 60. Genetic counseling includes all of the following EXCEPT: A Assessment of the occurrence or recurrence risk B Discussion of the impact of the disease on the patient and familyC Discussion of available genetic testing D Recommendation of specific reproductive options E Discussion of available therapies 61. To establish a successful and cost-effective screening program for detecting heterozygous carriers of an autosomal recessive disease, all of the following are essential, EXCEPT: A Reproductive options are available B Genetic counseling is provided with the testing C The screening test has a positive predictive value of 100% D A high-risk population can be identified E The disease is severe enough to be clinically significant 62. G6PD deficiency is common in African, Mediterranean, and Asiatic populations in which malaria has been endemic. Multiple different mutations have been found in different populations. This high frequency of G6PD mutations is best explained by: (Biochemical and Molecular Genetics of Human Disease) A Genetic drift. B Balanced polymorphism. C The mild phenotype of G6PD deficiency. D Founder effect. E The influence of drugs that cause hemolytic anemia.

63. Severe b-thalassemia may not become clinically apparent until a child is several months old because: A The a-globin genes don't turn on until several months after birth. B The oxygen needs of a newborn are minimal. C The g (gamma) to b-globin switch is not complete until several months after birth. D Elevated hemoglobin A2 compensates for the missing b-globin genes. E Overexpression of z-globin (zeta) compensates for the missing b-chain. 64. An alpha-thal silent carrier man (aa/a-) mates with an alpha-thal trait woman (aa/--). Assuming no genetic recombination, which of the following is NOT a possible genotype of their offspring? A a-/-- B a-/a- C aa/a- D aa/-- E aa/aa 65. In the pedigree below, all individuals in generation I have a-thalassemia trait. I-1 is of African descent. The child of II-2 died of hydrops fetalis. What are the most likely possible phenotypes of II-1?

A HbH disease, or hydrops fetalis. B Normal, or silent carrier. C Normal, a-thalassemia trait, or hydrops fetalis. D a-thalassemia trait only. E Silent carrier, or HbH disease.

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