A. Autosomal dominant
B. Autosomal recessive
C. Autosomal dominant with sex limitation
D. X-linked dominant
E. X-linked recessive
Clinical
9. Which one of the following statements concerning familial adenomatous polyposis (FAP) is correct?
A. Testing of the adenomatous polyposis coli (APC) gene is cost-effective in identifying carriers of the APC gene mutation among at-risk relatives of individuals with FAP
B. First-degree relatives should be screened with DNA sequencing of p53
C. Persons with the APC gene mutation develop colorectal adenomas after the age of 30 years
D. FAP is an autosomal recessive disorder
E. Patients with an identified APC mutation should have a colonoscopy every 3 years
10. A 25-year-old Cambodian woman who is known to have mild and non-symptomatic anaemia associated with beta-thalassaemia trait presents for counselling regarding the inheritance risk for her children. She is about to marry a 28-year-old Cambodian man who has no symptoms but has recently been tested and also been found to have beta-thalassaemia trait. Which one of the following is the probability that they will have an unaffected child without either beta-thalassaemia or beta-thalassaemia trait?
A. 0.01
B. 0.1
C. 0.25
D. 0.5
E. 0.75
11. Which one of the following changes in genomic stability contributes to the development of colorectal cancer?
A. Chromosomal instability involves inactivation of genes required for repair of mismatches in DNA bases
B. Chromosomal instability causes the loss of a wild-type copy of APC, a tumour suppressor gene
C. Germline defect in mismatch-repair genes is the main explanation for familial adenomatous polyposis
D. Amplification of gene copy number occurs commonly in colorectal cancer
E. Gene rearrangement occurs commonly in colorectal cancer
12. Which one of the following statements is correct regarding Down syndrome?
A. Alzheimer-like changes in the brain develop in mid-life
B. Both males and females are infertile
C. Temporal lobe epilepsy occurs in 40% of individuals
D. The commonest chromosomal abnormality is translocation
E. Individuals have a higher risk of developing acute myeloid leukaemia but not acute lymphoblastic leukaemia
13. A 36-year-old man has parasthesiae in his hands and feet. On examination, he has diffuse cutaneous angiokeratomas, which are particularly predominant on the buttocks, upper thighs, lower abdomen and peri-umbilical area. He has a systolic murmur in the aortic area. Echocardiography reveals asymmetrical left ventricular hypertrophy and left ventricular outflow tract obstruction. What is the most likely diagnosis?
A. Fabry disease
B. Neurofibromatosis
C. Niemann–Pick disease
D. Tay–Sachs disease
E. Marfan syndrome
14. Which one of the following diseases exhibits genetic anticipation?
A. Familial hypercholesterolaemia
B. Friedreich ataxia
C. Myotonic dystrophy
D. Tuberous sclerosis
E. Von Willebrand disease
15. Which one of the following correctly describes the haemochromatosis (HFE) gene and iron-overload disease?
A. HFE gene mutation in hereditary haemochromatosis type I is inherited in an autosomal dominant manner
B. H63D mutation homozygotes are a common (>90%) finding in individuals with hereditary haemochromatosis
C. C282Y mutation homozygotes develop iron-overload disease before 30 years of age
D. HFE gene mutations can lead to impairment in the hepcidin–ferroportin axis
E. Disease penetration in homozygotes for C282Y mutation is high (>75%)
16. A 22-year-old woman is referred for review because her 50-year-old father has been diagnosed with Huntington disease. She wants to know what this means for her. What is the most appropriate information for this patient?
A. She may have inherited the gene for Huntington disease, but it usually manifests in men only
B. There is a 50% chance that she has inherited the gene for Huntington disease; if she has, she is likely to show symptoms at a younger age than her father
C. There is a 50% chance that she has inherited the gene for Huntington disease, but if she has, she is likely to develop symptoms at an older age than her father
D. There is a 50% chance that she has inherited the gene for Huntington disease, but fewer than half of the people with the gene develop the disease
E. She is a carrier of the gene for Huntington disease, but she is unlikely to get the disease herself unless it runs in her mother’s family also
17. Which one of the following occurs in Klinefelter syndrome?
A. Normal fertility
B. Decreased testosterone concentrations
C. Hirsutism
D. Small stature
E. Reduced gonadotrophin concentrations
18. A 23-year-old man with a family history of acute intermittent porphyria (AIP) presents with abdominal pain and constipation. What is the best initial screening test for AIP in this man?
A. Spot urinary porphobilinogen (PBG) excretion during an attack
B. Erythrocyte porphobilinogen deaminase (PBGD)
C. DNA testing for ferrochelatase mutations
D. Faecal haem levels
E. Provocation test with phenobarbitone
19. A 39-year-old woman presents with a significant pneumothorax needing intercostal chest drain. She is known to have had epilepsy since the age of 16 years and mild cognitive impairment. She complained of left-sided loin pain and had a computed tomography (CT) abdomen which showed multiple, predominantly fat-density renal lesions suggestive of angiomyolipomas in both kidneys. An image from her previous chest CT is shown below. What is the most likely diagnosis?
A. Von Hippel–Lindau syndrome
B. Birtt–Hogg–Dubé syndrome
C. Tuberous sclerosis
D. Prader–Willi syndrome
E. Marfan syndrome
20. Which one of the following diseases involves genomic imprinting?
A. Angelman syndrome
B. Down syndrome
C. Fragile X syndrome
D. Huntington disease
E. Motor neurone disease
21. Which one of the following conditions is often found in female patients with a 45, X karyotype?
A. Hypertrophic cardiomyopathy
B. Hyperthyroidism
C. Carcinoma
D. Spontaneous fertility
E. Sensorineural hearing loss
Theme: Genetic inheritance (for Questions 22–25)
A. Autosomal dominant
B. Autosomal recessive
C. X-linked dominant
D. X-linked recessive
E. Y-linked
F. Co-dominant
G. Mitochondrial inheritance
H. Genomic imprinting
For each of the following conditions, select the correct mode of genetic inheritance from the options above.
22. What is the pattern of inheritance for type 1 von Willebrand disease?
23. What is the pattern of inheritance for alpha-1-anti-trypsin deficiency?
24. What is the pattern of inheritance for Leber hereditary optic neuropathy?
25. What is the pattern of inheritance for Duchenne muscular dystrophy?
Answers
Basic Science
1. Answer E
The DNA nucleotides are the purines adenine and guanine, and the pyrimidines cytosine and thymine. Uracil is the base that takes the place of thymidine in RNA. Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. Translation is the generation of protein from mRNA.
Topoisomerase is an enzyme involved in changing the amount of supercoiling of DNA and is required for many processes involving DNA, such as DNA replication and transcription. Fluoroquinolone antibiotics act by disrupting the function of bacterial topoisomerases, whilst several chemotherapeutic agents involved in cancer treatment are mammalian topoisomerase inhibitors, including topotecan and doxorubicin.
Base and histone modifications are involved in DNA gene expression, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases.
Ionising radiation can produce oxidative lesions in DNA, the most dangerous of which are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions and deletions and chromosomal translocations.
The DNA nucleotides are the purines adenine and guanine, and the pyrimidines cytosine and thymine. Uracil is the base that takes the place of thymidine in RNA. Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. Translation is the generation of protein from mRNA.
Topoisomerase is an enzyme involved in changing the amount of supercoiling of DNA and is required for many processes involving DNA, such as DNA replication and transcription. Fluoroquinolone antibiotics act by disrupting the function of bacterial topoisomerases, whilst several chemotherapeutic agents involved in cancer treatment are mammalian topoisomerase inhibitors, including topotecan and doxorubicin.
Base and histone modifications are involved in DNA gene expression, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases.
Ionising radiation can produce oxidative lesions in DNA, the most dangerous of which are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions and deletions and chromosomal translocations.
2. Answer D
Wilson disease is an autosomal recessive disease. Patients with an autosomal disease are represented using ‘aa’ ” or ‘a2’ as shown in the table below. In this case, a2 = 1/8100 (a = 1/90). The sum of frequencies of the dominant and recessive genes equals 1 (A + a = 1). As a result, A = 1 − a = (1 − 1/90) = 89/90. The carrier rate = 2 × A × a = 2 × 89/90 × 1/90. To simplify the calculation, 89/90 approximates to 1. As a result, the carrier rate equals 2 × A × a = 2 × 1 × 1/90 = 1/45.
These calculations assume that the population is at Hardy–Weinberg equilibrium and, for example, there is no survival advantage or disadvantage in utero. It can be expressed as a2 + A2 + 2Aa = 1
Wilson disease is an autosomal recessive disease. Patients with an autosomal disease are represented using ‘aa’ ” or ‘a2’ as shown in the table below. In this case, a2 = 1/8100 (a = 1/90). The sum of frequencies of the dominant and recessive genes equals 1 (A + a = 1). As a result, A = 1 − a = (1 − 1/90) = 89/90. The carrier rate = 2 × A × a = 2 × 89/90 × 1/90. To simplify the calculation, 89/90 approximates to 1. As a result, the carrier rate equals 2 × A × a = 2 × 1 × 1/90 = 1/45.
| A | a | |
| A | AA (normal gene) | Aa (carrier) |
| a | Aa (carrier) | aa (diseased) |
3. Answer E
HIV is a single-stranded RNA virus. Such viruses use reverse transcriptase to generate double-stranded DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host processes, such as transcription and translation, to reproduce the virus. Reverse transcriptase enzymes are inhibited by anti-retroviral drugs such as zidovudine and tenofovir.
MicroRNAs are short (20–22 nucleotides) RNA molecules that bind to complementary sequences in the downstream region of multiple target mRNAs, usually resulting in their decreased expression or translation. Their importance in the control of gene expression is being increasingly recognised.
Transfer RNA (tRNA) is a small RNA chain of about 80 nucleotides that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. It has sites for amino acid attachment and an anti-codon region for codon recognition that binds to a specific sequence on the messenger RNA chain through hydrogen bonding.
Ribosomes are the sites of protein biosynthesis, the process of translating mRNA into protein. Certain antibiotics such as chloramphenicol and aminoglycosides exert their anti-bacterial effects by binding to and inhibiting bacterial ribosomes.
HIV is a single-stranded RNA virus. Such viruses use reverse transcriptase to generate double-stranded DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host processes, such as transcription and translation, to reproduce the virus. Reverse transcriptase enzymes are inhibited by anti-retroviral drugs such as zidovudine and tenofovir.
MicroRNAs are short (20–22 nucleotides) RNA molecules that bind to complementary sequences in the downstream region of multiple target mRNAs, usually resulting in their decreased expression or translation. Their importance in the control of gene expression is being increasingly recognised.
Transfer RNA (tRNA) is a small RNA chain of about 80 nucleotides that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. It has sites for amino acid attachment and an anti-codon region for codon recognition that binds to a specific sequence on the messenger RNA chain through hydrogen bonding.
Ribosomes are the sites of protein biosynthesis, the process of translating mRNA into protein. Certain antibiotics such as chloramphenicol and aminoglycosides exert their anti-bacterial effects by binding to and inhibiting bacterial ribosomes.
4. Answer B
Epigenetics is defined as heritable changes in gene expression that are not attributable to alterations in the sequence of DNA (Hamilton, 2011). The predominant epigenetic mechanisms are DNA methylation, modifications to chromatin structure, loss of imprinting and non-coding RNA. An important feature of epigenetic modifications is that they are heritable between mother and daughter cells (mitotic inheritance) and between generations (meiotic inheritance). Epigenetics is one of the explanations for how cells and organisms with identical DNA can have such dramatic phenotypic differences (such as caterpillars and butterflies).
DNA methylation is the covalent addition or subtraction of a methyl group to a cytosine nucleotide in a sequence of DNA. Hypermethylation also occurs as a normal physiological process, e.g. during inactivation of the second X chromosome (Barr body) in females (lyonisation). The inactive X chromosome (Xi) is characterised by high levels of DNA methylation, low levels of histone acetylation, low levels of histone H3 lysine-4 methylation and high levels of histone H3 lysine-9 methylation, all of which are associated with gene silencing. These processes are guided by the X-inactive specific transcript (Xist) gene, which encodes a large non-coding RNA that is responsible for mediating the specific silencing of the X chromosome from which it is transcribed. The inactive X chromosome is coated by Xist RNA, whereas the active X chromosome (Xa) is not. In addition, hypermethylation is a physiological process associated with ageing and methylation-induced transcriptional repression of repetitive DNA elements helps to prevent chromosomal instability.
Epigenetics is defined as heritable changes in gene expression that are not attributable to alterations in the sequence of DNA (Hamilton, 2011). The predominant epigenetic mechanisms are DNA methylation, modifications to chromatin structure, loss of imprinting and non-coding RNA. An important feature of epigenetic modifications is that they are heritable between mother and daughter cells (mitotic inheritance) and between generations (meiotic inheritance). Epigenetics is one of the explanations for how cells and organisms with identical DNA can have such dramatic phenotypic differences (such as caterpillars and butterflies).
DNA methylation is the covalent addition or subtraction of a methyl group to a cytosine nucleotide in a sequence of DNA. Hypermethylation also occurs as a normal physiological process, e.g. during inactivation of the second X chromosome (Barr body) in females (lyonisation). The inactive X chromosome (Xi) is characterised by high levels of DNA methylation, low levels of histone acetylation, low levels of histone H3 lysine-4 methylation and high levels of histone H3 lysine-9 methylation, all of which are associated with gene silencing. These processes are guided by the X-inactive specific transcript (Xist) gene, which encodes a large non-coding RNA that is responsible for mediating the specific silencing of the X chromosome from which it is transcribed. The inactive X chromosome is coated by Xist RNA, whereas the active X chromosome (Xa) is not. In addition, hypermethylation is a physiological process associated with ageing and methylation-induced transcriptional repression of repetitive DNA elements helps to prevent chromosomal instability.
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