Multiple-Choice Answers

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CHAPTER 2: The Cellular and Molecular Basis of Inheritance

1 Base substitutions:

a True. When a stop codon replaces an amino acid
b True. For example, by mutation of conserved splice donor and acceptor sites
c False. Silent mutations or substitutions in non-coding regions may not be pathogenic
d True. For example promoter mutations may affect binding of transcription factors
e False. Frameshifts are caused by the insertion or deletion of nucleotides

2 Transcription:

a False. During transcription mRNA is produced from the DNA template
b True. The mRNA product is then translocated to the cytoplasm
c True. The mRNA is complementary to the antisense strand
d False. Transcription factors bind to regulatory sequences within the promoter
e True. The addition of the 5′ cap and 3′ poly(A) tail facilitates transport to the cytoplasm

3 The following are directly involved in DNA repair:

a True. The DNA glycosylase MYH is involved in base excision repair (BER)
b True. They incorporate the correct bases
c True. They seal gaps after abnormal base excision and correct base insertion
d False. Splicing removes introns during mRNA production
e False. Ribosomes are involved in translation

4 During DNA replication:

a True. It unwinds the DNA helix
b False. Replication occurs in both directions
c True. These fragments are joined by DNA ligase to form the lagging strand
d False. DNA replication is semiconservative as only one strand is newly synthesized
e False. Uracil is incorporated in mRNA, thymine in DNA

CHAPTER 3: Chromosomes and Cell Division

1 Meiosis differs from mitosis in the following ways:

a True. During human meiosis, the number of chromosomes is reduced from 46 to 23
b False. Early cell divisions in gametogenesis are mitotic; meiosis occurs only at the final division
c True. In meiosis, the two divisions are known as meiosis I and II
d True. The bivalents separate independently during meiosis I, and crossovers (chiasmata) occur between homologous chromosomes
e False. The five stages of meiosis I prophase are leptotene, zygotene, pachytene, diplotene, and diakinesis

2 Chromosome abnormalities reliably detected by light microscopy include:

a True. An extra chromosome (e.g., chromosome 21 in Down syndrome) is easily seen
b True. A missing chromosome (e.g., Turner syndrome in females with a single X) is easily seen
c False. A subtle translocation may not be visible
d False. A small deletion may not be visible
e True. Centric fusion of the long arms of two acrocentric chromosomes is readily detected

3 Fluorescent in situ hybridization using whole-chromosome (painting) or specific locus probes enables routine detection of:

a False. Changes in gene dosage may be identified by comparative genomic hybridization (CGH)
b True. Subtelomeric probes are useful in the investigation of non-specific learning difficulties
c True. Trisomies can be detected in interphase cells
d True. The origin of marker chromosomes can be determined by chromosome painting
e True. Subtle rearrangements can be detected by chromosome painting

4 Chemicals used in the preparation of metaphase chromosomes for analysis by light microscopy include:

a True. Colchicine inhibits spindle formation, thus arresting cells at metaphase
b True. Phytohemagglutinin stimulates cell division of T lymphocytes
c True. Giemsa is used to stain chromosomes a pink/purple color
d False. Quinacrine is a fluorescent stain not visible by light microscopy
e True. Hypotonic saline swells the cells, causing cell lysis and spreading of chromosomes

CHAPTER 4: DNA Technology and Applications

1 The following statements apply to restriction enzymes:

a True. Double-stranded DNA can be digested to give overhanging (sticky) ends or blunt ends
b False. More than 300 restriction enzymes have been isolated from various bacteria
c True. If the mutation creates or destroys a recognition site
d True. DNA digestion by a restriction enzyme is the first step in Southern blotting
e False. They are endonucleases as they digest DNA fragments internally, as opposed to exonuclease digestion from the 5′ or 3′ ends of DNA fragments

2 The following describe polymerase chain reaction (PCR):

a True. Millions of copies of DNA can be produced from one template without using cloning vectors
b False. PCR uses the heat-stable Taq polymerase, because a high denaturing temperature (around 95°C) is required to separate double-stranded products at the start of each cycle
c True. PCR may be used to amplify DNA from single cells (e.g., in preimplantation genetic diagnosis); therefore, appropriate control measures are important to avoid contamination
d False. PCR routinely amplifies targets of up to 1 kb and long-range PCR is limited to around 40 kb
e False. Knowledge of the sequence is required to design primers to flank the region of interest

3 Types of nucleic acid hybridization include:

a True. Southern blotting describes the hybridization of a radioactively labeled probe with DNA fragments separated by electrophoresis
b True. Hybridization between the target and probe DNA takes place on a glass slide
c False. Western blotting is used to analyze protein expression using antibody detection methods
d True. Northern blotting is used to examine RNA expression
e True. DNA fingerprinting employs a minisatellite DNA probe to hybridize to hypervariable DNA fragments

4 The following techniques can be used to screen genes for unknown mutations:

a True. Sequencing can be used to detect known or unknown mutations and will characterize an unknown mutation
b True. SSCP is an inexpensive method for mutation screening although its sensitivity is limited
c True. DHPLC is an efficient method for detecting heterozygous mutations
d False. Oligonucleotide ligation assay is used to detect known mutations as the probe design is mutation specific
e False. Real-time PCR is also used to detect known mutations as the probe design is mutation specific

CHAPTER 5: Mapping and Identifying Genes for Monogenic Disorders

1 Positional cloning uses:

a True. Now that the human genome sequence is complete, it is possible to identify a disease-associated gene in silico
b True. After a gene has been mapped to a region, it can be helpful to check for syntenic regions in animal models
c True. Many genes have been identified through mapping of translocation or deletion break-points
d False. Positional cloning describes the search for genes based on their chromosomal location
e True. A genome-wide scan uses microsatellite markers located throughout the genome for linkage mapping

2 A candidate gene is likely to be a disease associated gene if:

a True. This implies causality
b True. This is strong evidence
c True. This excludes the possibility that a single variant is a marker in linkage disequilibrium rather than a pathogenic mutation
d True. For example, a gene associated with blindness might be expected to be expressed in the eye
e False. A pseudogene does not encode a functional protein and mutations are therefore unlikely to be pathogenic

3 Achievements of the Human Genome Project include:

a False. The draft sequence was completed in 2000, but its publication date was February 2001
b True. Sequencing was finished 2 years ahead of the original schedule
c True. Annotation tools such as Ensembl were developed to assist users
d False. Nearly 1500 have been identified to date
e True. Around 5% of the US budget for the Human Genome Project was devoted to studying these issues

CHAPTER 6: Developmental Genetics

1 In development, HOX genes:

a True. They are important in spatial determination and patterning
b False. Only a few malformation syndromes can be directly attributed to HOX gene mutations at present, probably because of paralogous compensation
c False. They contain an important conserved homeobox of 180 bp
d True. They are probably important only in early development
e True. Where malformation-causing mutations have been identified, different organ systems may be involved, e.g., the hand–foot–genital syndrome (HOXA13)

2 In the embryo and fetus:

a False. This occurs later and is the process of laying down the primary body axis in the second and third weeks
b False. Organogenesis takes places mainly between 4 and 18 weeks’ gestation
c True. The genes in these pathways are expressed widely throughout the body
d False. Somites form in a rostro-caudal direction
e True. When mutated these genes lead to the ulnar–mammary syndrome and Holt-Oram syndrome

3 Concerning development pathways and processes:

a False. It is formed from the first pharyngeal (branchial) arch
b True. Remodeling occurs so that these vessels become the great arteries
c True. This has been established in animals and is proving to be highly likely in humans
d False. Achondroplasia is associated with very specific FGFR3 mutations affecting the membrane-bound part of the protein
e False. These different types of mutation usually cause widely differing phenotypes (e.g., the RET gene)

4 Regarding the X-chromosome:

a True. Sometimes the SRY gene is involved in recombination with the pseudoautosomal regions of X and Y
b False. Not all regions of the X are switched off; otherwise, there would presumably be no phenotypic effects in Turner syndrome
c True. However, only when there is a mutated gene on one X chromosome does this have any consequences
d False. SRY has an important initiating function, but other genes are very important
e True. Some unusual phenomena occur in twins leading to the conclusion that these processes are linked

5 Transcription factors:

a False. They are usually proteins that bind to specific regulatory DNA sequences
b False. They also switch genes on
c True. For example, a leg might develop in place of an antenna
d False. Transcription factors are crucial to normal laterality
e True. The zinc finger motif encodes a finger-like projection of amino acids that forms a complex with a zinc ion

CHAPTER 7: Patterns of Inheritance

1 Concerning autosomal recessive inheritance:

a False. Sex ratio is equal
b False. The risk at the time of conception is image
c True. All people carry mutated genes; cousins are more likely to share a mutated gene inherited from a common grandparent
d True. Affected individuals would have to partner a carrier or another affected person for their offspring to be affected as well
e False. The mechanisms causing Angelman syndrome are varied but autosomal recessive inheritance is not one of them

2 Concerning X-linked inheritance:

a True. A father passes his Y chromosome to his son
b True. He might have affected grandsons through his daughters who are carriers
c False. Although the condition affects females, the males are more severely affected because the female has a normal copy of the gene on her other X chromosome, and X-inactivation means that the normal copy is expressed in about half of her tissues
d True. All daughters of an affected man will be affected, but none of his sons
e False. Germline mosaicism always needs to be considered when an isolated case of an X-linked condition occurs

3 In mitochondrial genetics:

a False. This refers to two populations of mitochondrial DNA, one normal, one mutated
b False. The opposite, probably because they replicate more frequently
c False. Any tissue with mitochondria can be affected
d True. If the affected woman’s oocytes contain only mutated mitochondria
e False. Many mitochondrial proteins are encoded by nuclear genes

4 Concerning terminology:

a False. The same disease caused by different genes—but not necessarily on different chromosomes
b False. The basic pattern of inheritance in pseudodominance is autosomal recessive
c True. A proportion of individuals with the mutated gene show no signs or symptoms
d True. Diseases showing anticipation demonstrate increased severity, and earlier age of onset, with succeeding generations
e False. Not a variation in severity (variable expression), but two or more apparently unrelated effects from the same gene

5 In inheritance:

a True. Both copies of a mutated gene can be passed to a child this way
b True. This explains a proportion of cases of Prader-Willi and Angelman syndromes
c False. Digenic inheritance refers to heterozygosity for two different genes causing a phenotype
d True. This explains presenile baldness and gout
e False. Only a small proportion

CHAPTER 8: Mathematical and Population Genetics

1 In applying the Hardy-Weinberg equilibrium, the following assumptions are made:

a False. The population should be large to increase the likelihood of non-random mating
b True. Consanguinity is a form of non-random mating
c True. The introduction of new alleles introduces variables
d True. In theory, if the population is small and donors are used many times this would introduce a form of non-random mating
e True. Migration introduces new alleles

2 If the population incidence of a recessive disease is 1 in 10,000, the carrier frequency in the population is:

a False.
b False.
c False.
d True. The carrier frequency is double the square root of the incidence
e False.

3 Heterozygote advantage:

a False. It refers to conditions that follow autosomal recessive inheritance
b True. The homozygote may show markedly reduced biological fitness (e.g., cystic fibrosis)
c True. People with sickle-cell trait are more able to remove parasitized cells from the circulation
d True. A process of selective advantage may be at work
e False. The presence of the allele in a population may indeed be a founder effect

4 Polymorphic loci:

a False. The alleles need have frequencies of only 1%
b True. They are crucial to gene mapping by virtue of their co-segregation with disease
c True. Linkage analysis using polymorphic loci may be the only way to determine genetic status in presymptomatic diagnosis and prenatal testing
d False. The association of polymorphic loci with disease segregation is key to calculating a logarithmic of the odds score
e False. They may be important (e.g., blood groups)

5 In population genetics:

a False. The incidence of the disease must also be known
b True. In autosomal recessive disease most of the genes in the population are present in unaffected heterozygotes
c True. In recessive conditions unaffected sibships will not be ascertained
d True. Basically, only males are affected and they always manifest the condition
e False. It is useful only when there is a common ancestor from both sides of the family, (i.e., inbreeding)

CHAPTER 9: Polygenic and Multifactorial Inheritance

1 Concerning autism:

a False. It is a neurodevelopmental disorder and no metabolic abnormalities are found
b False. This would imply autosomal dominant inheritance. The rate is about 20%
c False. Although autism occurs in fragile X syndrome the vast majority of affected individuals do not have this condition
d True. The figure is nearly 3% for full-blown autism and a further 3% for milder features—autistic spectrum disorder
e False. The male : female ratio is approximately 4 : 1

2 Linkage analysis is more difficult in multifactorial conditions than in single-gene disorders because:

a True. Detection of polygenes with small effects is very difficult
b True. In a fully penetrant single-gene disorder, it is easier to find families with sufficient informative meioses
c True. Parametric linkage analysis requires that the mode of inheritance is known
d True. Different genetic and environmental factors may be involved
e True. The late age of onset means that affection status may be uncertain

3 Association studies:

a True. The disease and variant tested may be common in a population subset but there is no causal relationship
b True. The TDT test uses family controls and thus avoids population stratification effects
c True. Replication of positive studies in different populations will increase the evidence for an association
d False. Association studies are used to test variants identified by gene mapping techniques, including affected sibling-pair analysis
e True. Variants with small effects may be missed if the patients and controls are not closely matched

4 Variants in genes that confer susceptibility to type 2 diabetes (T2DM) have been found:

a True. The calpain-10 gene was identified by positional cloning in Mexican-American sibling pairs
b False. No confirmed T2DM susceptibility genes have been identified by this approach
c True. Examples include two subtypes of maturity-onset diabetes of the young (MODY)
d True. The genes encoding the potassium channel subunits in the pancreatic β-cell were biological candidates
e True. For example, the HNF-1A variant G319S has been reported only in the Oji Cree population

5 Variants in the NOD2/CARD15 gene:

a False. Evidence to date supports a role in Crohn disease, but not ulcerative colitis
b True. Increased risk is estimated at 40-fold for homozygotes and 2.5-fold for heterozygotes
c True. A genome-wide scan for inflammatory bowel disease (IBD) initially identified the 16p12 region
d False. The NOD2/CARD15 gene activates NF-κB, but this complex is already targeted by the most effective drugs used to treat Crohn disease
e False. The three reported variants are found at a frequency of 5% in the general population, compared with 15% in patients with Crohn disease

CHAPTER 10: Hemoglobin and the Hemoglobinopathies

1 For different hemoglobins:

a True. The population should be large to increase the likelihood of non-random mating
b False. This is true for the α and γ chains only; the β chain appears toward the end of fetal life
c False. There are too few α chains, which are replaced by β chains
d False. It is a form of α-thalassemia
e False. They have a mild anemia and clinical symptoms are rare

2 Regarding sickle-cell disease:

a False. The effect is due to reduced solubility and polymerization
b True. Obstruction of arteries can be the result of sickling crises
c True. A valine residue is substituted for a glutamic acid residue
d False. Life-threatening sepsis can result from splenic infarction
e True. These mutations give rise to an amino acid substitution

3 Concerning hemoglobin variants:

a True. This applies to the majority of those known
b False. All types of mutation are known
c False. Bone marrow hyperplasia occurs, which leads to physical changes such as a thickened calvarium
d True. Oxygen is not released so readily to tissues
e True. Hb H, for example, is unstable

4 Regarding hemoglobins during life:

a False. It is a hereditary condition
b False. This is true only between about 2 and 7 months’ gestation
c False. The bone marrow starts producing Hb from 6 to 7 months of fetal life
d False. Production ceases from 2 to 3 months of postnatal life
e True. It gives rise to no symptoms—the Hb chains produced are normal

CHAPTER 11: Biochemical Genetics

1 In congenital adrenal hyperplasia (CAH):

a True. The most common enzyme defect is 21-hydroxylase deficiency
b True. This occurs in the rare forms: 3β-dehydrogenase, 5α-reductase, and desmolase deficiencies
c True. Hyponatremia and hyperkalemia may be severe and lead to circulatory collapse
d False. Cortisol and fludrocortisone are required lifelong in salt-losing CAH
e False. Fertility is reduced in the salt-losing form

2 Phenylketonuria:

a False. There is a benign form as well as abnormalities of cofactor synthesis
b False. Dietary restriction of phenylalanine is necessary only during childhood and pregnancy
c True. These are features if untreated
d True. Affected individuals have reduced pigment and are fair
e False. A different pathway

3 Hepatomegaly is an important feature of:

a True. Hepatomegaly is a feature of most of the mucopolysaccharidoses
b True. Hepatomegaly is a feature of most of the glycogen storage disorders, although not all
c False. This is not a feature, even in the so-called hepatic porphyrias
d True. This is one of the sphingolipidoses—lipid storage diseases
e False. Cirrhosis can occur in the untreated

4 Concerning mitochondrial disorders:

a False. The main patterns of inheritance also apply where mitochondrial proteins are encoded by nuclear genes
b True. Especially in NARP and MIDD, respectively
c True. There are 37 gene products
d False. Leigh disease is genetically heterogeneous
e True. The G4.5 gene is mutated, urinary 3-methyglutaconic acid is raised, but the link remains to be elucidated

5 Regarding metabolic conditions:

a True. The carnitine cycle is important for long-chain fatty acid transport into mitochondria
b True. 90% of alleles are due to the same mutation and neonatal population screening has been suggested
c False. These are inborn errors of copper transport metabolism
d True. These features should prompt investigation for organic acidurias and mitochondrial disorders, among others
e False. Important radiological features may be seen in peroxisomal and storage disorders

CHAPTER 12: Pharmacogenetics

1 Thiopurine drugs used to treat leukemia:

a True.
b True. They are used to treat autoimmune disorders and to prevent rejection of organ transplants
c False. They can be toxic in 10% to 15% of patients
d True. These include leukopenia and severe liver damage
e True. Variants in the TPMT gene are associated with thiopurine toxicity

2 Liver enzymes that show genetic variation of expression and hence influence the response to drugs include:

a True. Complete deficiency of this enzyme causes type 1 Crigler-Najjar disease
b False. N-acetyltransferase (NAT2) variation influences the metabolism of isoniazid
c False. Absence of ALDH2 (acetaldehyde dehydrogenase) is associated with an acute flushing response to alcohol
d True. Approximately 5% to 10% of the European population is poor metabolizers of debrisoquine because of a homozygous variant in the CYP2D6 gene
e True. CYP2C9 variants are associated with decreased metabolism of warfarin

3 The following have an increased risk of complications from anesthesia:

a True. Malignant hyperthermia is dominantly inherited
b True. RYR1 mutations are associated with malignant hyperthermia
c False. G6DP deficiency results in sensitivity to certain drugs and fava beans
d True. Homozygous CHE1 mutations cause suxamethonium sensitivity
e False. Pseudocholinesterase metabolizes suxamethonium; therefore, decreased levels are associated with suxamethonium sensitivity

4 Examples of diseases in which treatment may be influenced by pharmacogenetics include:

a False. Patients with glucokinase mutations are usually treated with diet alone
b True. Patients with HNF1A mutations are sensitive to sulfonylureas
c True. Abacavir is an effective drug but approximately 5% of patients show potentially fatal hypersensitivity
d True. Some patients show adverse reactions to the drug felbamate
e True. Slow inactivators of isoniazid are more likely to suffer side effects

CHAPTER 13: Immunogenetics

1 Concerning complement:

a False. The cascade can also be activated by the alternative pathway
b True. C4 levels are reduced and production of C2b is uncontrolled
c False. C3 levels are normal, C4 levels are reduced
d True. C3b adheres to the surface of microorganisms
e False. Complement is a series of at least 20 interacting plasma proteins

2

a False. It is made up of four polypeptide chains—two ‘light’ and two ‘heavy’
b False. They are distributed around different chromosomes
c False. Donors are likely to share HLA haplotypes, which are crucial to tissue compatibility
d True. These are variable, diversity, junctional and constant regions
e True. Antigen receptors contain two immunoglobulin-like domains

3

a False. They are protected for only 3 to 6 months
b False. X-linked SCID is 50% to 60% of the total
c True. B-cell positive SCID due to JAK3 deficiency can be subclinical
d True. A defect in either T-cell function or development
e False. CGD is an X-linked disorder of cell-mediated immunity

4

a False. It is classed as a secondary or associated immunodeficiency
b True. Immunodeficiency is usually mild and the immune system improves with age as the thymus grows; there is a proneness to viral infections in childhood
c False. The causes of common invariable immunodeficiency are not known and it is often a disorder of adult life
d False. The risk to first-degree relatives is increased but the pedigree pattern is more suggestive of multifactorial conditions
e True. FTT may be the only clue to an immunodeficiency disorder

CHAPTER 14: Cancer Genetics

1

a True. The best known example is chronic myeloid leukemia and the Philadelphia chromosome
b False. Tumor suppressor genes are more common than oncogenes
c True. Apoptosis is normal programmed cell death
d False. LOH refers to the presence of two defective alleles in a tumor suppressor gene
e False. Although important, APC mutations are part of a sequence of genetic changes leading to colonic cancer

2

a True. The paradigm was retinoblastoma and the hypothesis was subsequently proved to be correct
b False. Mutations in TP53 are found in many cancers, but are germline in Li-Fraumeni syndrome
c False. It is implicated in MEN-2, but not MEN-1
d True. There is a significant risk of small bowel polyps and duodenal cancer
e True. Women with this condition have a lifetime risk of up to 50%

3

a True. This syndrome is allelic with Cowden disease, in which papillary thyroid cancer can occur
b True. The lifetime risk may be in the region of 16%
c False. The BRCA1 and BRCA2 genes do not account for all familial breast cancer
d False. The lifetime risk of breast cancer for female BRCA1 or BRCA2 carriers is 60% to 85%
e False. The figure is approximately 15%

4

a False. Cerebellar hemangioblastoma is a common tumor in VHL
b False. This tumor is seen in MEN-2 and VHL disease
c True. There is also an increased risk in familial breast cancer
d True. Melanin spots in Peutz-Jegher syndrome, basal cell carcinomas in Gorlin syndrome, and skin tumors in the Muir-Torre form of HNPCC
e False. The figure is approximately one-third

5

a True. Clear cell renal carcinoma is a significant risk in VHL
b False. It is easier to detect breast cancer by mammography in postmenopausal women
c False. It should begin at birth
d False. This does not meet the Amsterdam criteria for HNPCC
e False. It is strongly indicated in FAP, but not in women positive for BRCA1 mutations

CHAPTER 15: Genetic Factors in Common Diseases

1

a False. The figure is approximately 40%
b True. One form of epilepsy is autosomal dominant, benign, familial neonatal convulsions
c False. This epilepsy is non-mendelian
d True. A large proportion of patients have epilepsy of different kinds, including infantile spasms
e False. It is mendelian (autosomal recessive) but is progressive with neurodegeneration

2

a False. The high risk is for schizophrenia
b False. The risk lies between 40% and 50%
c True. This is the case despite many studies suggesting significant linkage
d True. The concordance rates in monozygotic and dizygotic twins are 67% and 20%, respectively
e False. Although present in about 40% of patients with Alzheimer disease, it is not discriminatory enough for screening

3

a True. Conversion of the prion protein to the abnormal isoform, PrPSc, is more likely
b True. The genes are APP, Presenilin-1, and Presenilin-2
c False. The penetrance is very high for all mendelian Alzheimer disease so far reported
d False. Epidemiological studies using twins have proved more important so far in answering this question
e True. However, the reasons are not entirely clear, despite the APP gene being located on chromosome 21

4 Hemochromatosis:

a True. Mutations in at least five genes can cause hemochromatosis
b False. Males are five times more likely to be affected
c True. Regular phlebotomy is an effective treatment
d False. Penetrance may be as low as 1%
e False. The most common cause is homozygosity for the C282Y HFE mutation

5 The following statements about venous thrombosis are true:

a True. They account for more than 50% of cases
b False. Unlikely, but their first-degree relatives can be offered testing and prophylactic treatment if necessary
c False. The factor V Leiden mutation renders the factor V protein resistant to cleavage by activated protein C
d True. Raised serum prothrombin levels result from the G20210A variant
e True. The risks are multiplicative

CHAPTER 16: Congenital Abnormalities and Dysmorphic Syndromes

1

a False. The figure is approximately 25%
b True. This is the figure from chromosome studies. It might be much higher if all lethal single-gene abnormalities could be included
c False. The figure is –3%
d False. This is an example of deformation
e True. ‘Sequence’ implies a cascade of events traced to a single abnormality

2

a False. Syndrome is correct because of the highly recognizable nature of the condition
b False. It has been found to be due to mutations in a single gene
c True. The figure varies between populations and is lowered by periconceptional folic acid
d False. This well defined entity is an autosomal recessive condition
e True. It may be chromosomal, autosomal dominant, and autosomal recessive

3

a True. A teratogen represents a chemical or toxic disruption
b True. Renal agenesis causes oligohydramnios, which leads to talipes through deformation
c False. A variety of limb defects can occur
d True. There is a generalized effect on a particular tissue, such as bone or skin
e False. The figure is much higher, at around 50%

4

a True. Deafness and various visual defects are features
b False. The first trimester is much more dangerous
c True. Vertebral defects at any level are possible, including sacral agenesis
d False. This is true for some populations, not all
e True. Peripheral pulmonary artery stenosis in the case of congenital rubella

5

a True. The incidence is between 1 in 500 and 1 in 1000
b False. Low recurrence risk because they are thought not to be genetic
c False. Large studies of many families are required
d True. Smith-Lemli-Opitz syndrome is a defect of cholesterol metabolism, affecting the sonic hedgehog pathway
e False. The figure is much nearer 1 in 100

CHAPTER 17: Genetic Counseling

1

a False. This is the consultand; the proband is the affected individual
b False. Retinitis pigmentosa can follow all the main patterns of inheritance
c False. It is far more—transfer of relevant information, presentation of options, and facilitation of decision making in the face of difficult choices
d False. Non-directive counseling is the aim because patients/clients should be making their own decisions
e True. Patients do not remember risk information accurately and there are other important measures of patient satisfaction

2

a False. The risk is approximately twice the background risk
b True. This is a second-degree relationship
c False. The risk is roughly 25%
d False. It is perfectly normal in many societies
e False. It refers to anything from, for example, uncle–niece partnerships (second degree) to third cousins (seventh degree)

3

a False. Guilt feelings from parents and grandparents are common when a genetic disease is first diagnosed in a child
b False. Many patients make the choice they would have made before genetic counseling—but after the counseling they should be much better informed
c True. The risk from each grandparent is 1 in 64
d False. Such a practice is strongly discouraged and the indications for genetic testing should be the same
e False. Good patient support groups have a huge role, and the patients/families themselves become the experts for their condition

CHAPTER 18: Chromosome Disorders

1

a True. Chromosome number was identified in 1956, DNA structure in 1953
b True. A wide variety of abnormal karyotypes occur in spontaneous abortuses but 45,X is the single most common one
c False. It is estimated that 80% of all Down syndrome fetuses are lost spontaneously
d True. Although the risk of Down syndrome increases with maternal age, the large proportion of babies born to younger mothers means that most Down syndrome babies are born to this group
e False. A small proportion has an IQ at the lower end of the normal range

2

a False. Such children usually die within days or weeks of birth
b True. Males with Klinefelter syndrome (47,XXY) are usually infertile
c True. This accounts for a substantial proportion of cases
d False. This is not seen in either uniparental disomy or imprinting center defect cases
e True. The deletion on 22q11.2 is a 3-Mb region flanked by very similar DNA sequences

3

a True. Probably because of haploinsufficiency for elastin
b False. Congenital heart disease is not a recognized feature of Prader-Willi syndrome
c False. Chromosome 11p13, and may be a feature of WAGR and Beckwith-Wiedemann syndrome
d True. A mutation in PAX6 or a deletion encompassing this locus at 11p15
e True. Behavioral phenotypes can be very informative (e.g., Smith-Magenis syndrome)

4

a False. The figure is approximately 1 in 1000
b False. IQ is reduced by 10 to 20 points but learning difficulties are not a feature
c True. The other cell line may be normal but could also contain Y-chromosome material
d False. They have normal fertility
e True. This occurs because of DNA instability

5

a True. The mutation passes from a normal transmitting male to his daughters essentially unchanged
b False. In addition to FRAXA, there is also FRAXE and FRAXF
c True. Androgen insensitivity syndrome can present in this way
d False. This is unreliable. DNA analysis is necessary
e False. The figure is around 5%

CHAPTER 19: Single-Gene Disorders

1

a False. Meiotic instability is greater in spermatogenesis than in oogenesis
b True. This has been shown from studies in Venezuela
c False. The duration is approximately 10 to 15 years
d True. This is so for the reduced penetrance alleles of 36 to 39 repeats
e True. The condition is due to a very large triplet repeat expansion, as in fragile X syndrome

2

a False. Somnolence is common
b False. Neonatal hypotonia
c True. Through a CUG RNA-binding protein, which interferes with a variety of genes
d True. An important feature of myotonic dystrophy and the defining abnormality of many channelopathies
e True. Males with mild or subclinical CF have congenital bilateral absence of the vas deferens

3

a False. The DF508 mutation is the most common
b True. The polythymidine tract—5T, 7T, and 9T—can be crudely correlated with different CF phenotypes
c False. This is true for most of the inherited cardiac arrhythmias; cardiomyopathies are often from defects in cardiac muscle proteins
d True. This glycoprotein complex in the muscle membrane contains a variety of units; defects in these cause various limb-girdle dystrophies
e False. These patients have normal intelligence

4

a False. They are good candidates according to current thinking
b False. It is only a component of the skeletal system criteria
c False. It is thought to be a fully penetrant disorder
d True. This is not usually severe but is a recognized feature
e False. The opposite is the case

5

a False. This is a neurophysiological classification
b True. Autosomal dominant, autosomal recessive and X-linked
c True. Mutations in the peripheral myelin protein affect Schwann cells
d False. They are not good discriminatory tests and DNA analysis is much preferred
e False. It is an inherited cardiac arrhythmia

CHAPTER 20: Screening for Genetic Disease

1

a True. By looking for evidence of two populations of cells
b True. Firm clinical signs are the exception rather than the rule
c False. DNA sequence variants must be polymorphic to be useful
d False. There is far too much locus heterogeneity in this condition
e True. As a general rule this may be vital, but should be undertaken with informed consent

2

a False. The facial rash of angiokeratoma (adenoma sebaceum) is often not present
b False. There may not be sufficient numbers of café-au-lait spots until age 5 to 6 years
c False. They may be fully informative of an individual’s genetic status
d True. Dural ectasia of the lumbar spine is one of the major criteria
e False. Linked DNA markers, and sometimes biochemical tests, may be the best modality available

3

a False. Participation should, in principle, be voluntary
b True. The outcome of population screening programs should be an improvement in health benefit
c False. This is the specificity of a test
d True. This is different from the sensitivity, which refers to the proportion of affected cases that are detected (i.e., there may be some false negatives)
e True. Adequate expert counseling should be part of the predictive test program

4

a True. Recall of the result itself, or the interpretation, is frequently inaccurate
b False. The highest incidence for a serious disease is that in β-thalassemia: 1 in 8 is carriers
c False. This has happened before and should be a major concern
d False. The benefit lies in informing the family for subsequent reproductive decisions
e False. The first assay is biochemical, a measure of immunoreactive trypsin

5

a False. Although the carrier frequency is about 1 in 10, no population screening is undertaken in the United Kingdom
b False. In general, unless a beneficial medical intervention can be offered, such testing should be deferred until the child is old enough to make the decision
c True. They have been operational for about 30 years
d False. This is only at the research stage
e False. Their prime function in a service department is for clinical management of patients and families

CHAPTER 21: Prenatal Testing and Reproductive Genetics

1

a False. It is still mainly performed around 16 weeks’ gestation
b False. They also derive from the amnion and fetal urinary tract epithelium
c True. The risk is 1% to 2%, compared with 0.5% to 1%
d False. There is a small risk of causing limb abnormalities; CVS should not be performed before 11 weeks’ gestation
e False. Fetoscopy is required for this if a DNA test is not available

2

a True. This forms part of the triple test
b True. This forms part of the triple test
c False. In trisomy 18 all maternal serum markers are low
d False. The best figure achieved is around 86%
e True. There are two fetuses rather than one

3

a False. The figure is about 1%
b True. Especially aneuploidies
c True. Probably because of the presence of inspissated meconium
d True. Most cases of Down syndrome are due to meiotic non-disjunction
e True. They are unlikely to have different clinical effects in different members of the same family

4

a False. A license from the HFEA is required
b False. It is not illegal but does require a HFEA license
c True. This is undertaken to avoid the presence of extraneous sperm
d False. The figure is about 25%
e False. Chromosome disorders are the largest group

5

a True. Chromosome abnormalities are present in 10% to 12% of men with azoospermia or severe oligospermia, some of them heritable
b False. The rule is that no more than 10 pregnancies may result from one donor
c False. They are currently not entitled to know the identity of their biological parents
d True. Analyzing fetal cells in the maternal circulation only removes the miscarriage risk
e False. The figure is approximately 1 in 7

CHAPTER 22: Risk Calculation

1

a True. These are two ways of expressing the same likelihood
b True. A probability of 1 means that the event will happen 100% of the time
c True. The probability that both will be boys is image, for girls the same; therefore the chance of being the same sex is image (0.5)
d True. These two approaches to a probability calculation are essential
e True. 70% of heterozygotes will manifest the condition

2 For an autosomal recessive condition the chance that the first cousin of an affected individual is a carrier is:

a False.
b False.
c True. The affected individual’s parents are obligates carriers, aunts and uncles have a 1 in 2 risk, cousins a 1 in 4 risk
d False.
e False.

3 In X-linked recessive inheritance:

a False. The risk is 1 in 2 if the sex of the fetus is known to be male
b False. The male might be affected because a new mutation has occurred
c True. This is significant and has to be allowed for in risk calculation and counseling
d True. This is conditional information that can be built into a Bayes’ calculation
e False. This is a key individual whose risk must be calculated before the consultand’s risk

4 In autosomal recessive inheritance the risk that the nephew of an affected individual, born to the affected individual’s healthy sibling, is a carrier is:

a False.
b False.
c False.
d True. The healthy sibling of the affected individual has a 2 in 3 chance of being a carrier; this person’s son has a risk which is half that
e False.

5

a True. For example, negative mutation findings when testing for cystic fibrosis
b True. Age of onset (clinical expression) data must be derived from large family studies
c False. Without this information huge errors will be made
d True. An empiric risk is really a compromise figure
e False. It may matter a lot because it is a measure of the likelihood that a meiotic recombination event will take place between the marker and the gene mutation causing the disease

CHAPTER 23: Treatment of Genetic Disease

1 Methods currently used to treat genetic disease include:

a False. Germ-cell gene therapy is considered unacceptable because of the risk of transmitting genetic changes to future generations
b True. For example, bone marrow transplantation is used to treat various inherited immunodeficiencies
c True. Examples include the replacement of factor VIII or IX in patients with hemophilia
d True. For example, restricted phenylalanine in patients with phenylketonuria
e False. This potential treatment has been tested in animal models

2 Gene therapy may be delivered by:

a True. Liposomes are widely used as they are safe and can facilitate transfer of large genes
b True. CFTR gene therapy trials have used adeno-associated viral vectors
c False. Antisense oligonucleotides need to be delivered to the target cells
d True. Lentiviruses may be useful for delivery of genes to non-dividing cells
e True. An example is the injection of plasmid-borne factor IX into fibroblasts from patients with hemophilia B

3 Gene therapy has been used successfully to treat patients with the following diseases:

a False. Trials have shown safe delivery of the CFTR gene to the nasal passages but effective treatment of cystic fibrosis is not possible at present
b True. A number of patients have been treated successfully, although concern was raised when two boys developed leukemia
c False. This will be difficult because the number of α- and β-globin chains must be equal or a thalassemia phenotype might result
d True. Some patients have been able to reduce their exogenous clotting factors
e True. Although early attempts were unsuccessful, two patients have now been treated successfully by ex vivo gene transfer

4 Potential gene therapy methods for cancer include:

a True. An example is the protein kinase inhibitor used to treat chronic myeloid leukemia
b True. Perhaps through overexpression of interleukins
c False. Anti-angiogenic factors might be used to reduce blood supply to tumors
d True. RNA interference is a promising new technique that can used to target overexpressed genes associated with cancers
e True. A number of trials are ongoing to determine the utility of this technique

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