Genetics

1. A 20-year-old woman presents with hypothyroidism. On further questioning it transpires she has primary amenorrhoea. She is also of relatively short stature compared to her sisters. What is the most likely diagnosis? Turners syndrome Your answer Downs syndrome Noonans syndrome XXX syndrome Achondroplasia

Although Turners syndrome (XO) and Downs and Noonans syndromes can be associated with short stature and hypothyroidism, Downs syndrome and Noonans syndrome are not associated with menstrual irregularities. Females with an extra X chromosome (XXX syndrome) are usually tall, whereas individuals with achondroplasia are usually very short; neither condition has an increased incidence of hypothyroidism or menstrual irregularities. The other typical features of Turners syndrome are cardiac defects (eg coarctation of the aorta), congenital lymphoedema, neck webbing, widely spaced nipples and cubitus valgus. Noonans syndrome is an autosomal-dominant condition (so it affects both sexes), and other typical features include pulmonary stenosis, neck webbing and low-set posteriorly rotated ears.

2. You are reviewing an 18-year-old woman with cystic fibrosis. How would the genetic inheritance of this condition best be described?

It has an autosomal-dominant mode of inheritance It has an X-linked dominant mode of inheritance It has an autosomal-recessive mode of inheritance Your answer It has an X-linked recessive mode of inheritance It is a chromosomal disorder Cystic fibrosis is an autosomal-recessive disorder, the carrier frequency in Caucasians being 1 in 22. There is a gene mutation on the long arm of chromosome 7, with the commonest abnormality being a deletion mutation at position 508 in the amino acid sequence. This causes a defect in the transmembrane conductance receptor (CFTR), a chloride channel. The result is increased tenacity and viscosity of secretions. Examples of autosomal-dominant disorders include neurofibromatosis and Marfans syndrome. Examples of X-linked disorders include CharcotMarieTooth disease and Alports syndrome. Examples of chromosomal disorders include Downs syndrome (trisomy 21) and Pataus syndrome (trisomy 13).

3. A 29-year-old man is referred to you with lethargy, constipation and generalised bone pain. Some 5 years ago he had pituitary surgery for a prolactinoma. He mentions that his father had required surgery to his thyroid a few years ago and his brother is currently in hospital with kidney stones. What is the most likely diagnosis? Pseudohypoparathyroidism Hypophosphataemia Familial hypocalciuric hypercalcaemia Multiple endocrine neoplasia type 1 Your answer Multiple endocrine neoplasia type 2 The clinical features are very suggestive of hypercalcaemia and the previous history of a pituitary tumour makes multiple endocrine neoplasia type 1 (MEN1) the most likely diagnosis. MEN1 is a dominantly inherited susceptibility to parathyroid adenomas, pituitary tumours and enteropancreatic endocrine tumours due to mutations in the MEN1 gene. Conversely, multiple endocrine

neoplasia type 2 (MEN2) is a dominantly inherited susceptibility to medullary thyroid cancer, parathyroid adenomas and phaeochromocytomas due to mutations in the RET gene. MEN2 is subdivided into MEN2A and MEN2B; MEN2B is associated with mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract and a Marfanoid body habitus. Pseudohypoparathyroidism is characterised by hypocalcaemia. Hypophosphataemia can be caused by primary or secondary hyperparathyroidism. Familial hypocalciuric hypercalcaemia is associated with moderate hypercalcaemia associated with an inappropriate low rate of urinary calcium excretion. None of these conditions are associated with pituitary tumours.

4. A 20-year-old man presents with pes cavus, distal weakness and wasting of his leg muscles, absent knee and ankle jerks and reduced sensation to touch and vibration in his feet and legs. His father is said to have similar problems. Nerve conduction studies show absent sensory potentials from his sural nerve and reduced motor nerve conduction velocities in his common peroneal nerve. What is the most likely diagnosis? Autosomal dominant cerebellar ataxia DejerineSottas syndrome Friedreichs ataxia Hereditary sensory and motor neuropathy type 1 (HMSN1) Hereditary neuropathy with liability to pressure palsies (HNPP)

Your answer

The history, clinical findings and result of nerve conduction studies in this man are consistent with the diagnosis of HMSN I. The family history is suggestive of an autosomal dominant disorder (male to male transmission). The clinical findings suggest that the patient has a mixed (motor and sensory) peripheral neuropathy and this is confirmed by the results of nerve conduction studies that show absent sensory potentials from the sural nerve and reduced motor nerve conduction velocity (NCV). The motor nerve conduction velocity is 38 m/s and therefore this patient has HMSN1. In patients with HMSN2 the motor NCVs are > 38 m/s, and patients with DejerineSottas syndrome have a very severe form of HMSN with delayed motor development, hypotonia, areflexia, ataxia, palpable peripheral nerves and motor NCVs < 10 m/s. Hereditary neuropathy with liability to pressure palsies is associated with a predisposition to recurrent common peroneal nerve and/or ulnar nerve palsy as a result of pressure or traction. This condition can also be associated with a mild generalised peripheral neuropathy.

5. A 45-year-old lady is referred to you with a diagnosis of renal cell carcinoma. She tells you that she had surgery for phaeochromocytoma at the age of 25 years. What is the most likely diagnosis? Familial paraganglioma Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2A (MEN2A) Neurofibromatosis type 1 (Nf1) Von HippelLindau disease

Your answer

This lady has von Hippel-Lindau (VHL) disease. This is an autosomal dominant cancer predisposition syndrome that is caused by mutations in the VHL gene on 3p25p26. Patients with this condition are at risk of developing cerebellar, brainstem and spinal haemangioblastomas, retinal angiomas, phaeochromocytomas and paragangliomas (extraadrenal phaeochromocytomas), renal cysts and clear cell renal cell carcinoma, pancreatic cysts and islet cell tumours, epididymal tumours and endolymphatic tumours. Renal cell carcinoma is the most common cause of death in this condition. The condition shows agedependant penetrance. Diagnostic criteria for VHL include:

the presence of two or more haemangioblastomas (retinal or CNS) the combination of a haemangioblastoma and a visceral manifestation of VHL in the absence of a family history the presence of one haemangioblastoma or visceral manifestation with a positive family history.

Phaeochromocytoma and paragangliomas can also be seen in patients with familial paragangliomas, MEN1, MEN2A, MEN2B and Nf1, but renal cell carcinoma is not a recognised feature of any of these conditions.

6. In which of the following hereditary conditions will affected males have a significant risk of fathering affected sons? Duchennes muscular dystrophy Cystic fibrosis

Myotonic dystrophy Your answer MELAS (myopathy, encephalopathy, lactic acidosis, stroke) Haemophilia type A Absence of male-to-male transmission is a hallmark of X-linked genetic conditions. In X-linked conditions none of the male offspring of an affected male will be affected or be carriers, whereas all his daughters will be carriers and themselves be at risk of having affected sons. In mitochondrial diseases neither male nor female offspring of an affected male will inherit as the mutated mitochondria are passed down in the female egg. Duchennes muscular dystrophy and haemophilia type A are both examples of Xlinked conditions, while MELAS is due to a mitochondrial mutation. Cystic fibrosis (CF) is an autosomal-recessive condition, so, in theory, a male with CF could have an affected son if his partner was a carrier. (The carrier frequency in northern Europeans is approximately 1 in 25.) However, in practice, males with CF are invariably infertile as congenital bilateral absence of the vas deferens (CBAVD) is a cardinal feature of CF. Myotonic dystrophy is an autosomaldominant condition and therefore there is a 50% risk to the male and female offspring of an affected male, therefore this is the correct answer.

7. Which of the following should be considered in the management of haemophilia A? The infant is protected at birth due to maternal transfer of factor VIII Desmopressin may be useful A factor VIII concentration < 10% causes severe disease Most cases are the result of new mutations von Willebrand factor levels are reduced

Your answer

Because factor VIII is not transferred through the placenta, bleeding may occur in severe cases. People with mild to moderate haemophilia respond to desmopressin sufficiently to cover minor procedures like tooth extraction. Less than a 2% level is associated with severe disease, which entails spontaneous bleeding into joints and muscles. Most cases are the result of X-linked recessive transmission. Probably one-third of cases may result from a new mutation. von Willebrand factor levels are normal.

8. You review a 64-year-old man who is on warfarin therapy for recurrent atrial fibrillation. He presents to the Accident and Emergency Department with bruising. An international normalised ration (INR) check reveals that his INR is raised, at 6.5. Which of the following drugs may result in increased INR when co-prescribed with warfarin therapy? Ciprofloxacin Phenobarbitone Carbamazepine Primidone Rifampicin Your answer

All of the other drugs are hepatic enzyme inducers and result in accelerated metabolism of warfarin and therefore reduced effect and decreased international normalised ratio (INR). Chloramphenicol, ciprofloxacin, clarithromycin, erythromycin, metronidazole, nalidixic acid, norfloxacin, ofloxacin, and sulphonamides are all associated with reduced warfarin metabolism and enhanced anti-coagulant effect. Tetracyclines and trimethoprim are not thought to have any definitive effect on INR. Anecdotal experience suggests that prolonged courses of broad-spectrum penicillins may affect INR.

9. A 38-year-old woman is sent as an emergency to you with an acute-onset headache and deteriorating conscious level. Her husband mentions that her brother has recently had a kidney transplant, although he is not sure why. What condition may be running in the family? von HippelLindau disease Hereditary haemorrhagic telangiectasia Polycystic kidney disease Your answer Alports syndrome Tuberous sclerosis

Intracranial aneurysms occur in approximately 10% of individuals with autosomaldominant polycystic kidney disease (ADPKD), and approximately 50% of patients with ADPKD have end-stage renal disease by age 60 years. It is a relatively common genetic disorder and there are two known ADPKD genes PKD1, accounting for about 85% of cases, and PKD2, accounting for about 15% of cases. von HippelLindau disease can cause renal cysts, renal carcinoma and cerebellar haemangioblastomas, but a history of renal transplant would be unusual. Cerebral atriovenous malformations can occur in hereditary haemorrhagic telangiectasia and these may result in intracerebral bleeding, but the kidneys are not typically involved. Alports syndrome causes renal failure and deafness. Renal cysts can be found in tuberous sclerosis (TS). In addition, there is a high frequency of subependymal glial nodules and cortical tubers, but these would not explain the history of sudden-onset headache.

10. colleague asks for your help in designing a new diagnostic molecular assay where small amounts of DNA need to be accurately amplified and analysed. Which would be your technique of choice? Southern blotting Immunoprecipitation Polymerase chain reaction (PCR) Your answer Western blotting Enzyme-linked immunoabsorbant assay (ELISA) PCR is a rapid and versatile method for amplifying defined target DNA sequences. It is one of the cornerstone techniques in molecular genetics and facilitates the rapid cloning and analysis of DNA. It uses a heat-stable polymerase enzyme originally derived from a species of thermophilic bacteria. A typical PCR reaction will takes 12 hours. It is a fast, sensitive and robust technique and has

been adapted for a multitude of different applications. Southern blotting is used in DNA analysis but does not amplify DNA. Western blotting, immunoprecipitation and ELISA are all techniques used in protein analysis.

11. The 3' 5' exonuclease activity possessed by some DNA polymerases that enables the enzyme to replace misincorporated nucleotide is called what? Proofreading Replication Recombination Retrotransposition Splicing Your answer

Retrotransposition is transposition via an RNA intermediate (transposition is the movement of a genetic element from one site to another in a DNA molecule). Splicing is the removal of introns from the primary transcript of a discontinuous gene.

12. A middle-aged woman is referred to you by her GP with a 6-month history of increasing breathlessness on exertion. Her son is affected with Duchennes muscular dystrophy, as was her brother. What would you be concerned about in her? Bronchiectasis Cardiomyopathy Your answer Emphysema Respiratory muscle failure Pericardial effusion Duchennes muscular dystrophy (DMD) is an X-linked condition that is typically

diagnosed in boys between the ages of 3 and 6 years. The boys have difficulty walking and develop calf pseudohypertrophy. They are typically wheelchairbound by early adolescence and are unlikely to live beyond 30 years, usually dying from cardiomyopathy or respiratory failure. Other complications include contractures, scoliosis, intellectual impairment and reduced night vision. The creatine phosphokinase is grossly elevated and the diagnosis can be made by muscle biopsy. Genetic testing will detect around two-thirds of mutations in the dystrophin gene. Because both her son and brother are affected with DMD, this woman is an obligate carrier. Female carriers can develop a proximal myopathy and there is a 1020% lifetime risk of cardiomyopathy.

13. An 18-year-old woman presents with mild polyuria and polydipsia; her fasting blood glucose concentration is 14 mmol/l. Her father and two of her three sisters have diabetes. She responds well to treatment with insulin, and is stabilised on a total dose of 14 units per 24 h. A mutation in which of the following is likely to be responsible for her condition? Glucokinase Glutamic acid decarboxylase Hepatic nuclear factor-1 Insulin Insulin promoter factor-1

Your answer

Given the strong family history and low insulin requirement, the presumptive diagnosis is maturity onset diabetes of the young (MODY). Five variants of this condition have been described, involving mutations in various hepatic nuclear factors, glucokinase and insulin promoter factor-1, but more than half of cases are associated with mutation in hepatic nuclear factor-1. Patients with type-1 diabetes often have islet cell antibodies in their plasma at the time of diagnosis: their antigens include insulin and glutamic acid decarboxylase but islet cell antibodies are not present in MODY.

14. Which one of the following inherited diseases is due to mutation in mitochondrial DNA? Alports syndrome Lebers optic neuropathy Your answer

Noonans syndrome Fabrys disease Marfans syndrome Prevalence of mitochondrial diseases equals 1:10000 of live-born infants. Mutations of mitochondrial DNA (mtDNA) are their most frequent cause. The diseases often result in encephalomyelopathy, cardiomyopathy, vision disorders, dysacusis and metabolic disorders. Despite numerous studies problems associated with mitochondrial diseases have not been completely solved yet. LHON (Lebers Hereditary Optic Neuropathy) was the first described disease associated with hereditary point mutations in mtDNA. The disease is characterised by subacute loss of binocular vision with a lesion of the central field of vision, improper colour vision and atrophy of optic nerve. Other examples include Kearns-Sayre syndrome which is caused both by deletions and duplications of mtDNA. The onset of disease symptoms is observed before 20 year of age. Short stature, pigmentary retinal degeneration, ophthalmoplegia, ptosis, ataxias, disturbances in conduction in heart muscle, diabetes, and hearing loss occur in the syndrome. The other example is CPEO (Chronic Progressive External Ophthalmoplegia) which may occasionally occur as a result of de novo mutation, may be maternally inherited (mt tRNA mutations) or can be of autosomally dominant inheritance. Symptoms of CPEO are ptosis, myopathy, depression, cataract and ketoacidosis. Alports syndrome, Noonans syndrome, Fabrys disease and Marfans syndrome are diseases caused by mutations in nuclear and not mitochondrial DNA.

15. A 25-year-old patient presents with anaemia and jaundice. A blood film shows polychromasia, bite cells, reticulocytosis and Heinz bodies. What is the most probable diagnosis? Haemolytic uraemic syndrome Autoimmune haemolytic anaemia Glucose-6-phosphate dehydrogenase deficiency Hereditary spherocytosis Paroxysmal nocturnal haemoglobinuria

Your answer

The blood picture, caused by haemolysis, is consistent with G6PD deficiency. Glucose-6phosphate dehydrogenase deficiency is the commonest red cell enzyme defect. Inheritance is sex-linked and the disease is common in Africa, the Mediterranean and the Middle and Far East. The majority are asymptomatic until there is an oxidative crisis precipitated by drugs (eg primaquin, sulfonamides, ciprofloxacin, quinidine, probenecid), fava bean ingestion or illness. Reticulocytosis is common and indicates active erythropoiesis. The presence of Heinz bodies is characteristic of G6PD deficiency. In hereditary spherocytosis, the red blood cells are usually spherical in shape. This is an autosomal dominant red cell membrane defect where the RBCs are osmotically fragile. Splenomegaly is common. Blood film shows spherocytes. Hereditary elliptocytosis has the same clinical features as hereditary spherocytosis with the presence of elliptocytic red cells on the blood film.

16. Genomic imprinting is seen in which of the following conditions? Neurofibromatosis PraderWilli syndrome Huntingtons chorea Hurlers syndrome Marfans syndrome

Your answer

The term 'genomic imprinting' refers to the dependence of phenotype on whether the gene deletion is inherited from the mother or father. Neurofibromatosis is an autosomaldominant disorder with 95% penetrance. The gene is located on chromosome 17. Prader Willi syndrome is a result of a paternal deletion of a gene on chromosome 15; Angelman syndrome results if the same gene is deleted from the maternal side. In both syndromes, 3 5% of cases are a result of uniparental disomy (both chromosomes from the same parent). Huntingtons chorea is a result of a triplet codon repeat. There is a 3590 repeat segment of CAG nucleotides on chromosome 4p 16.3. It is rare in childhood, presenting later in adult life with dementia, chorea and rigidity. Hurlers syndrome (type I) is an autosomalrecessive disorder occurring due to a defect in chromosome 4p. Marfans syndrome is an autosomal-dominant disorder affecting chromosome 15q.

17. You see a healthy 20-year-old man in your clinic. There is no significant past medical history and he plays rugby for Saracens rugby club. He tells you that his brother died at the age of seven years with cystic fibrosis. What are his chances of being a carrier? 1 in 4 (25%) 1 in 3 (33%)

1 in 2 (50%) 2 in 3 (67%) 3 in 4 (75%)

Your answer

Cystic fibrosis (CF) is an autosomal recessive disorder that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on 7q31.2. Affected individuals have mutations in both alleles of this gene. The siblings of an affected individual have:

a 1 in 4 (25%) chance of being affected with this condition a 1 in 2 (50%) chance of being CF carriers a 1 in 4 (25%) chance of being neither affected nor a carrier.

The proband in this question is a healthy 20-year-old man and he is therefore unaffected with CF. When affected siblings are removed from the above equation then the unaffected siblings have a 2 in 3 (67%) chance of being CF carriers and 1 in 3 (33%) chance of not being carriers.

18. You review a 28-year-old man with a family history of early thyroid carcinoma and phaeochromocytoma. Your patient has been searching on the internet and has found information about the RET proto-oncogene. The proto-oncogene RET causes which thyroid cancer? Papillary Medullary Follicular Anaplastic Lymphoma

Your answer

Mutations of the RET proto-oncogene on chromosome 10 are associated with multiple endocrine neoplasia (MEN) 2a and 2b. MEN2a is associated with phaeochromocytoma, Cushings syndrome, medullary thyroid carcinoma, and parathyroid hyperplasia. MEN2b is similar, but patients have a marfanoid habitus and intestinal and visceral ganglioneuromas, but not hyperparathyroidism. Rarely, it may occur in isolation without other tumours. Screening for medullary thyroid carcinoma is with the pentagastrin and the calcium infusion test with measurement of calcitonin. Where there is a family history of MEN2, total thyroidectomy in childhood to prevent the development of carcinoma is usually recommended. Prior to consideration of thyroidectomy, screening for co-existent phaeochromocytoma is essential, so that alpha-blockade can be considered, otherwise the risk of on-table hypertensive crisis is high.

19. Multiple members from a large family suffer from an autosomal-dominant disorder. Although the gene for the condition is known, a mutation has not been found in the family. One of the family members wants to know if he will develop the disease as his father is affected. Blood samples are available from both affected and unaffected members. Which molecular technique is most useful in this situation? DNA sequence analysis Linkage analysis Your answer Southern blotting Microarray analysis Chromosome analysis It is quite common for a gene mutation not to be found in a family even though the gene for the condition is known. Often this is due to the limitations of mutation screening (although sometimes a mutation in a different gene might cause the same phenotype). If a reasonable number of samples are available from affected and unaffected members of a family then linkage analysis can be performed using microsatellite markers. By testing both affected and unaffected members, the allele carrying the mutation can be tracked through the family. DNA sequencing and Southern blotting are mutation detection techniques and microarray analysis is a gene expression technique. Chromosome analysis is used to look at gross chromosome structure rather than gene analysis.

20. Which of the following disorders may have an autosomal recessive mode of inheritance? Achondroplasia Glucose 6-phosphate dehydrogenase deficiency

Huntingtons disease EhlersDanlos syndrome Type IV Haemophilia A

Your answer

EhlersDanlos syndrome is a autosomal recessive heritable disorder of connective tissue with easy bruising, joint hypermobility (loose joints), skin laxity, and weakness of tissues. There are a number of different types of EhlersDanlos syndrome (EDS) which share the foregoing features but can be categorised into at least nine different types. Type IV may be inherited in autosomal recessive or dominant fashion. 21. A 35-year-old man is referred to you with altered bowel habit and weight loss. One of his sisters had a hysterectomy for uterine cancer aged 42, another sister had colorectal cancer aged 44 and his father died from colorectal cancer in his fifties. Colonoscopy shows a few polyps and a caecal mass. Which genetic condition might be running in the family? Familial adenomatous polyposis PeutzJeghers disease Neurofibromatosis type 1 von HippelLindau disease Hereditary non-polyposis colorectal cancer Your answer Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal-dominantly inherited predisposition to colorectal cancer in the absence of florid polyposis. There are two main forms, Lynch I (no family history of other cancers) and Lynch II (with other cancers in the family, eg endometrial, ovarian, urinary tract). It is diagnosed according to the Amsterdam criteria: families must have at least three relatives over two generations with colorectal cancer, one a first-degree relative of the other two, with at least one case being diagnosed below the age of 50 years. These criteria were originally devised for research purposes and lessstringent criteria are often used in clinical practice. At least six genes are known to cause HNPCC and they are involved in repairing DNA-sequence mismatches. Familial adenomatous polyposis is characterised by profuse colonic adenomatous polyposis. Affected individuals develop hundreds of polyps by their second decade and have a greatly increased risk of colorectal cancer. PeutzJeghers

syndrome is characterised by melanin flecks on the lips and mucocutaneous borders with a hamartomatous polyposis, and is associated with an increased risk of colorectal cancer. As only a few polyps were found on colonoscopy both of these conditions would be less likely than HNPCC. Neither neurofibromatosis type 1 or 2 nor von HippelLindau disease are associated with an increased risk of colorectal cancer.

22. What is the most likely diagnosis in a 30-year-old man with tall stature, gynaecomastia and azoospermia? Cystic fibrosis Homocystinuria Klinefelters syndrome Marfans syndrome XYY syndrome

Your answer

Tall stature is a feature of Homocystinuria, Klinefelter syndrome, Marfans syndrome and XYY syndrome. The combination of tall stature, gynaecomastia and infertility due to azoospermia is diagnostic of Klinefelters syndrome. Almost all males with Klinefelter syndrome are azoospermic. Other features of this condition include reduced facial hair, tendency to obesity, and small atrophic testes. Mild learning difficulties can be seen in some patients with Klinefelters syndrome but mental retardation is not a feature of this condition. Chromosome analysis will show 47 chromosomes, with two X and one Y chromosome (47, XXY). Patients with Homocystinuria have tall stature, learning difficulties, lens dislocation osteoporosis and recurrent arterial thrombosis. Features of Marfans syndrome include tall stature, arachnodactyly, scoliosis, joint laxity, lens dislocation, aortic root dilatation, dural ectasia, skin striae, and recurrent pneumothorax. The XYY syndrome is characterised by tall stature, mild learning difficulties and behavioural problems. Most males with this condition have normal fertility, although a small proportion of patients will have infertility due to azoospermia.

23. A 16-year-old boy presented with absence of pubertal development. On examination he was tall, his voice was unbroken, testes were undescended and there was only scanty pubic hair. What is the diagnosis? Klinefelters syndrome Turners syndrome Your answer

Kallmanns syndrome Testicular feminisation Hypopituitarism Klinefelters syndrome affects around 1 in 1000 males and is a chromosome disorder associated with 47XXY. Phenotypical changes include poor sexual development, small or undescended testes, scanty pubic hair, gynaecomastia and infertility. The disease involves both the loss of Leydig cells and seminiferous tubular dysgenesis. Androgen replacement restores secondary sexual characteristics, but no treatment is possible for the infertility. Confirmation of the disorder is by chromosomal analysis.

24. You see a 20-year-old girl with ataxia and restricted eye movements in the clinic. She tells you that she developed bilateral hearing loss at the age of nine years, retinitis pigmentosa at 10 years, and insulin-dependent diabetes mellitus at 15 years. When she was 18 years old she had a pacemaker inserted for complete heart block. What is your diagnosis? Friedreichs ataxia KearnsSayre syndrome Myotonic dystrophy Spinocerebellar ataxia (SCA) type 7 Usher syndrome

Your answer

This patients clinical features are typical of KearnsSayre syndrome, which is a mitochondrial disorder characterised by rearrangements of mitochondrial DNA, including deletions and duplications. The clinical features that suggest a mitochondrial disorder include any combination of sensorineural hearing loss, retinitis pigmentosa, muscle weakness, ataxia, recurrent stroke, cardiomyopathy, insulin-dependent diabetes mellitus, complete heart block and lactic acidosis. The tissues involved in mitochondrial disorders are those that depend heavily on oxidative phosphorylation for energy production. KearnsSayre syndrome is the only mitochondrial disorder of the five possible answers provided. Other mitochondrial disorders include myoclonic epilepsy and ragged red fibres (MERRF); and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (together known as MELAS).

25. A patient has been diagnosed with Marfans syndrome. Which gene mutation is responsible for this condition? Fibrillin Mitochondria Cyclooxygenase Hexosaminidase Galactosidase Your answer

Marfans syndrome is characterised by a triad of features:

long, thin extremities frequently associated with other skeletal changes, such as loose joints and arachnodactyly reduced vision as the result of dislocations of the lenses (ectopia lentis) aortic aneurysms that typically begin at the base of the aorta.

Most patients can be identified by detection of mutations in the fibrillin gene.

26. A 20-year-old man is referred for investigation of hypogonadism and infertility. He went through normal puberty and there is no significant family history. On examination he is tall with gynaecomastia and small testes. He has a normal sense of smell. Which condition would be high on your list of differential diagnoses? Klinefelters syndrome Your answer XYY syndrome Marfans syndrome Kallmanns syndrome Fragile X syndrome

This is due to the addition of an extra X chromosome (XXY). It is the most common sex chromosome abnormality (1 in 600 male births) and the most common cause of male hypogonadism and infertility. Affected males tend to be tall and can have mild learning difficulties, although many have normal intellect. XYY, Fragile X and Marfans syndromes are not associated with hypogonadism or infertility. Fragile X syndrome is associated with macro-orchidism and moderate to severe learning disability. Kallmanns syndrome is associated with anosmia and hypogonadotrophic hypogonadism (as opposed to hypergonadotrophic hypogonadism in Klinefelters syndrome).

27. When is a gene mutation causing a particular genetic disorder said to be highly penetrant? It affects a large number of the population Affected individuals with the same mutation have a very similar phenotype Individuals with the mutation invariably develop the phenotype The disorder only manifests early in life It affects both sexes equally

Your answer

The penetrance is the proportion of individuals with the gene who show the phenotype, eg Huntingtons disease shows a high penetrance as individuals with the mutation invariably develop the disorder. The expression is the degree to which the disorder is expressed in the individual; for example, neurofibromatosis type 1 has a very variable expression, in that individuals can manifest in a variety of ways ranging from mild to severe.

28. Which of these are well-recognised late complications of trisomy 21 (Downs syndrome)? Ischaemic heart disease Addisons disease Alzheimers dementia Your answer Glioblastoma Cataracts

Individuals with Downs syndrome have a greatly increased risk of developing Alzheimers dementia. Virtually 100% will show neuropathological changes by the age of 3540 years, and the average age of onset of clinical features is 5154 years. Hypothyroidism is common in Downs syndrome and should always be considered as a differential diagnosis. There is also an increased risk of leukaemia. None of the other conditions listed above are well-recognised late complications.

29. A 40-year-old man is referred to you with breathlessness and bradycardia. During the consultation you notice that he has a bilateral ptosis. He is estranged from his family and never knew his father, but he does know that his sister has a muscle problem and lost a child in infancy. What diagnosis might you suspect in this man? Duchennes muscular dystrophy Facioscapulohumeral dystrophy Beckers muscular dystrophy

Myotonic dystrophy Your answer Spinal muscular atrophy Myotonic dystrophy is an autosomal-dominant neuromuscular disorder caused by an expansion in a triplet repeat in the DMPK gene. There is a rough correlation between the expansion size and the severity of the phenotype. Clinical features include myopathic facies, ptosis, myotonia, cataracts, testicular atrophy and diabetes mellitus. Cardiac conduction defects of varying degrees of severity are common. The disease exhibits anticipation (a progressively severe phenotype with each generation) due to the expansion of the triplet repeat. It is possible his sisters child had congenital myotonic dystrophy, a very severe form of the condition due to a massive expansion in the triplet repeat that is inherited from the affected mother. The other listed conditions are not associated with ptosis, although cardiac problems (typically cardiomyopathy) can occur in Duchennes muscular dystrophy and its milder variant, Beckers muscular dystrophy. Duchennes muscular dystrophy usually results in death by the third decade. Facioscapulohumeral dystrophy is characterised by a pattern of muscle weakness involving the face, scapula, upper arm, lower leg and hip girdle. Spinal muscular atrophy is an autosomal-recessive condition usually affecting children, but there is a milder adult version (type IV) which causes a proximal myopathy.

30. A 35-year-old man presents with severe hypertension and is found to have a unilateral phaeochromocytoma. His father died from metastatic renal-cell carcinoma aged 48 and previously had surgery for a brain tumour. What is the most likely underlying genetic condition? Neurofibromatosis type 1 Multiple endocrine neoplasia type 2A von HippelLindau syndrome Your answer Hereditary haemorrhagic telangiectasia

Neurofibromatosis type 2 Phaeochromocytomas are said to follow the rule of 10: 10% are malignant, 10% are bilateral, 10% are extra-adrenal and 10% are familial. Genetic conditions associated with phaeochromocytomas include neurofibromatosis type 1 (NF1), multiple endocrine neoplasia type 2 (MEN2) and von HippelLindau syndrome (VHL), all are autosomal-dominant. Individuals with NF1 can be diagnosed using criteria based on the clinical features of caf-au-lait spots, axillary freckling, Lisch nodules and neurofibromas. The most serious complications in adults with NF1 are hypertension due to either renal artery stenosis or phaeochromocytomas and malignant transformation of the neurofibromas. MEN2, due to mutations in the RET gene, is characterised by medullary thyroid cancer, parathyroid hyperplasia and phaeochromocytomas (type 2A) and rarely with a marfanoid habitus and mucosal neuromas (type 2B). Complications of the VHL syndrome include phaeochromocytomas, renal-cell carcinomas and retinal and cerebellar haemangioblastomas, which can cause intracerebral haemorrhage. VHL syndrome is therefore the most likely genetic condition in this case and the patient and other close family members should be screened for haemangioblastomas and renal-cell carcinomas in addition to phaeochromocytomas. DNA analysis will detect VHL gene mutations in over 90% of VHL families. Phaeochromocytomas are not associated with hereditary haemorrhagic telangiectasia (HHT) or neurofibromatosis type 2 (NF2). However, brain tumours (vestibular schwannomas, gliomas, meningiomas) are a feature of NF2 and cerebral arteriovenous malformations are sometimes seen in patients with HHT.

31. A 25-year-old adopted man consults for review. He is interested in having children and is concerned about the possibility of inheritance of genetic disease. Which of the following is most prevalent in northern Caucasians? Cystic fibrosis 1-antitrypsin deficiency (AT) Congenital hypothyroidism Sickle cell disease Phenylketonuria

Your answer

AT is inherited as an autosomal dominant disorder and 1 in 10 northern Europeans carry an abnormal gene. This is in contrast to cystic fibrosis causes AT is located on chromosome 14. Gene mutations are characterised by their electrophoretic properties as slow (S), medium (M) or very slow (Z). The S and Z variants are associated with clinical disease. 1Antitrypsin deficiency is characterised by both early development of emphysema (which may be accelerated further by smoking) and cirrhosis of the liver.

32. In which of the following genetic diseases is DNA analysis useful? Adult polycystic kidney disease Downs syndrome Huntingtons disease Hyperobstructibe coronary myopathy Klinefelders syndrome

Your answer

Single-gene disorder (also called Mendelian or monogenic) is caused by changes or mutations that occur in the DNA sequence of one gene. Genes code for proteins, the molecules that carry out most of the work, perform most life functions, and even make up the majority of cellular structures. When a gene is mutated so that its protein product can no longer carry out its normal function, a disorder can result. There are more than 6000 known single-gene disorders, which occur in about 1 out of every 200 births. Some examples are cystic fibrosis, sickle cell anaemia, Marfans syndrome, Huntingtons disease, and hereditary haemochromatosis.

33. A 40-year-old man develops jerky movements affecting various parts of his body. His father died at the age of 55 and had been diagnosed as having Huntingtons disease. Which of the following genetic abnormalities is responsible for this condition? Frame-shift mutation Point mutation Splicing mutation Termination mutation Triplet-repeat mutation Your answer Huntingtons disease, an autosomal-dominant disease, is caused by a triplet-repeat mutation, with expansion (typically 4055 repeats) of a CAG triplet. This gives rise to a long sequence of glutamine residues in a protein of unknown function called huntingtin. Huntingtons disease may demonstrate genetic anticipation with an increasingly early onset in succeeding generations: this is due to an increase in the number of triplet repeats. Huntingtons disease is inevitably fatal.

The other types of mutation listed can all cause mutations in proteins as a result of the insertion of the wrong amino acid (point and frame-shift mutations); incorporation of amino acid sequences not normally present (splicing mutations) or premature or late termination of transcription (termination mutations).

34. A patient has been investigated for loose joints. He also complains of reduced vision. On examination he has very thin extremities and arachnodactyly. What is the most likely diagnosis? Marfans syndrome TaySachs disease Fabry disease Gaucher disease NiemannPick disease Marfans syndrome is characterised by a triad of features:

Your answer

long, thin extremities frequently associated with other skeletal changes, such as loose joints and arachnodactyly reduced vision as the result of dislocations of the lenses (ectopia lentis) aortic aneurysms that typically begin at the base of the aorta.

35. You are asked to review a young man with short stature, short fifth metacarpals, subcutaneous calcification, intellectual impairment and hypocalcaemia. Given the likely clinical diagnosis, mutation resulting in the dysfunction of what structure is most likely? An ion-channel linked to the PTH receptor A G-protein linked to the PTH receptor Your answer A tyrosine kinase receptor A tyrosine phosphatase receptor A serine kinase receptor There are, broadly speaking, three types of membrane-bound receptors, which can be subclassified according to the mechanism they use to activate signalling molecules. They are ion channel-linked receptors, G protein-linked receptors and enzyme-linked receptors.

When the G protein-linked receptor is activated by a ligand it binds a trimeric complex (alpha, beta and gamma) which is anchored to the inner surface of the plasma membrane. This trimeric compound is called a GTP-binding protein or G-protein. The G-protein receptor then binds GTP (guanosine triphosphate), and interacts with enzymes on the inner membrane surface to activate one of a number of secondary messengers. Secondary messengers activated may include cyclic AMP, calcium ions or inositol 1,4,5triphosphate/diacylglycerol. Pseudohypoparathyroidism is caused by mutation in a G-protein linked to the PTH receptor. Variable degrees of resistance may also be seen to other G protein-linked hormones including TSH, LH and FSH.

36.Which of the following statements is true in the epidemiology of 1-antitrypsin deficiency? Smoking is not a major risk factor There is an increased incidence of hyper-reactive airways in adult life It is an autosomal dominant disorder with low penetrance The disorder is an indication for liver transplantation in a child Most cases present during the neonatal period

Your answer

1-antitrypsin deficiency is an autosomal recessive disorder. Emphysema results from the uncontrolled action of the proteases on the lung tissue. There is accelerated age-related decline in FEV1, which is exacerbated by smoking. Smoking is the greatest risk factor for the development of panacinar emphysema in adults with 1-antitrypsin deficiency. In nonsmokers this may never develop or occur later in life. Jaundice and cirrhosis occur because the hepatocytes are unable to secrete the protein. Progressive liver damage in an infant in the neonatal period is an indication for liver transplant.

37. A 26-year-old teacher of Ashkenazi Jewish descent presents with long-standing bone pain. On examination there is marked hepatosplenomegaly. Which genetic disorder should be included in the list of differential diagnoses? TaySachs disease Canavans disease NiemannPicks disease type A Galactosaemia Gauchers disease Your answer Gauchers disease is a recessively inherited deficiency of the enzyme glucocerebrosidase,

which leads to an accumulation of glucosylceramide in lysosomes. It is the most common lysosomal storage disease. Clinical features include hepatosplenomegaly, anaemia and osteopenia. Type 1 disease is the most common and is characterised by the lack of neurological involvement. It can affect both children and adults and mild forms can first present in adulthood. It is most prevalent in the Ashkenazi Jewish population and can be treated with enzyme replacement therapy. Types 2 and 3 are associated with neurological involvement. TaySachs, Canavans and NiemannPicks disease are all also more common in the Ashkenazi Jewish population but all result in severe intellectual impairment. TaySachs and NiemannPicks disease type A (which both have a macular cherry-red spot that is a useful diagnostic aid) result in death in early childhood, whereas the life expectancy for those with Canavans disease can be into the teens. Galactosaemia is not more prevalent in the Ashkenazi Jewish population; it usually presents in neonates with hypoglycaemia and acidosis and is associated with progressive hepatosplenomegaly, cataracts and intellectual impairment.

38. You are asked to see a 19-year-old man who has had recurrent pneumothoraces. He is tall with pes planus and has an increased arm span to height ratio and upper segment to lower segment body ratios. Which other feature would be most helpful in making a diagnosis of Marfans syndrome? Joint hypermobility High arched palate Mid-systolic click Arachnodactyly Early diastolic murmur Your answer Marfans syndrome is an autosomal-dominant syndrome caused by mutations in the fibrillin-1 gene (FBN1) on chromosome 15q21 with an incidence of 12 per 10,000. Some 25% are new mutations and the gene is large and polymorphic, which make diagnostic genetic testing problematic. The diagnosis is therefore

currently made on clinical criteria. These cover the skeletal, eye, cardiac, respiratory and skin systems and are divided into major and minor criteria. Although arachnodactyly, high arched palate, mitral valve prolapse and joint hypermobility are all features of Marfans syndrome, they are relatively nonspecific (minor criteria). On the other hand, an early diastolic murmur indicates aortic valve incompetence, which is likely to be secondary to aortic root dilatation, a major feature of Marfans syndrome. This is the most serious complication of Marfans syndrome and affected individuals require annual cardiology assessments. Other major skeletal features include chest wall deformities (pectus carinatum or pectus excavatum, requiring surgery), a reduced upper segment to lower segment ratio, an arm span to height ratio > 1.05, a scoliosis of > 20 degrees and pes planus. Lens dislocation (usually upwards) is found in 5080% of affected individuals.

39. The substitution of the amino acid valine instead of the normal glutamic acid at position 6 of the -globin chain is the genetic abnormality encountered in which one of the following types of congenital haemolytic anaemia? Sickle cell anaemia Your answer -Thalassaemia Hereditary spherocytosis Glucose-6-phosphate dehydrogenase (G6PD) deficiency Methaemoglobinaemia Haemolytic anaemia is either congenital or acquired: Congenital haemolytic anaemia Membrane defect: hereditary spherocytosis Enzyme defects: (G6PD) deficiency Haemoglobin defects: thalassaemia, sickle cell anaemia Sickle cell anaemia is due to the inheritance of a gene for a structurally abnormal -globin chain subunit of adult haemoglobin, HbS. The abnormal

haemoglobins are caused by amino acid substitutions in their polypeptide chains. The amino acid valine replaces glutamic acid at position 6 of the -globin chain. -Thalassaemia is due to failure to synthesise beta chains. Hereditary spherocytosis and G6PD are not disorders of -globin chain. Methaemoglobin results from NADH-methaemoglobin reductase deficiency which causes the iron atom to be oxidized to the ferric (Fe3+) form, rendering the molecule incapable of binding an oxygen molecule. It causes persistent cyanosis without hypoxia. It does not cause haemolysis.

40. A 25-year-old woman presents with primary hyperparathyroidism. It emerges that she has been treated previously for a prolactinoma. What is your diagnosis? Familial parathyroid hyperplasia Multiple endocrine neoplasia type 1 Neurofibromatosis type 1 Polyglandular autoimmune syndrome type 1 von HippelLindau syndrome

Your answer

The history of primary hyperparathyroidism and a pituitary tumour in this patient is diagnostic of multiple endocrine neoplasia type 1 (MEN1). This is an autosomal dominant disorder that is caused by mutations in the MEN1 gene on 11q13. It is characterised by tumours of the parathyroid glands, pituitary and pancreatic islet cells. About 90% of patients develop parathyroid hyperplasia or adenoma. Pituitary tumours are seen in about 60% of patients. They include prolactinomas, growth hormone-producing tumours and ACTH-producing tumours. Between 5075% of patients with MEN1 develop pancreatic islet cell tumours that include gastrinoma, insulinoma, glucagonoma and VIPoma. Most patients with MEN1 present with hypercalcaemia due to primary hyperparathyroidism. Presenting features of pituitary tumours can include galactorrhoea and infertility (due to prolactinoma), acromegaly or Cushings disease. Pancreatic islet cell tumours can present with ZollingerEllison syndrome (due to gastrinoma), watery diarrhoea with hypokalaemia and metabolic acidosis or VernerMorrison syndrome (due to VIPoma), recurrent hypoglycaemia (due to insulinoma), and hyperglycaemia and necrolytic migratory erythema (due to glucagonoma). The MEN1 gene encodes a tumour suppressor protein called MENIN.

41. Angelmans and PraderWilli syndromes both involve defects in the same chromosome region. What is the best molecular explanation for differences in the phenotypes in these two conditions? It is sex-linked with the PraderWilli syndrome, occurring mainly in boys It is due to anticipation, with successive generations becoming more severely affected It is related to the degree of X chromosome inactivation It is due to modifying genes on other chromosomes It is due to the differential expression of genes depending on parental Your origin answer Imprinting is a mechanism that results in differential gene expression according to parental origin. It is responsible for a number of genetic syndromes, the best known of which are the Angelmans and PraderWilli syndromes. Angelmans syndrome causes ataxia and severe learning disability and is caused by absent maternal expression of the 15q1113 chromosome region. Conversely, the PraderWilli syndrome (mild/moderate learning disability, hyperphagia and obesity) is caused by absent paternal expression of the 15q1113 chromosome region. Other syndromes caused by imprinting abnormalities include the BeckwithWiedermann syndrome (macroglossia, abdominal wall defects, hypoglycaemia, visceromegaly) and the RussellSilver syndrome (small stature). The exact mechanism of imprinting is not well understood but is thought to involve differential gene methylation. Both Angelmans and PraderWilli syndromes occur with equal frequency in both sexes. Anticipation is a completely different genetic mechanism where trinucleotide repeat expansions cause increasingly severe phenotypes in successive generations. Variations in X chromosome inactivation are thought to partly explain the mild phenotypes sometimes seen in female carriers of X-linked disorders. While modifier genes may well explain phenotypic variation between individuals with the same syndrome, they do not explain the differences between the Angelmans and PraderWilli syndromes.

42. A 19-year-old woman is referral to you with a blood pressure of 180/130 mmHg. On examination she has caf-au-lait patches and some axillary freckling. She required surgery for scoliosis as a child. What is the most likely underlying diagnosis? Marfans syndrome Neurofibromatosis type 1 Your answer

Hypertrophic cardiomyopathy Tuberous sclerosis Cushings disease Neurofibromatosis type 1 (NF1) is an autosomal-dominant condition diagnosed in an individual who has met two or more of the following criteria: 1 Six or more caf-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals Two or more neurofibromas of any type or one plexiform neurofibroma Freckling in the axillary or inguinal regions Optic glioma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion, such as sphenoid dysplasia or thinning of the longbone cortex with or without pseudarthrosis A first-degree relative (parent, sibling, or offspring) with NF1 as defined by the above criteria

2 3 4 5 6 7

NF1 is due to mutations in the NF1 gene on chromosome 17q11, and is one of the most commonly dominantly inherited conditions. Hypertension can be caused by renal artery stenosis or phaeochromocytomas. Other complications include optic gliomas, vertebral dysplasia, pseudarthrosis, intracranial tumours and malignant peripheral nerve-sheath tumours. About half of the people with NF1 have a learning disability. Tuberous sclerosis is associated with hypopigmented macules, periungual fibromas, facial angiofibromas and shagreen patches (raised connective tissue lesions usually on the lower back). Other features include cortical tubers in the brain, learning disability, epilepsy and renal angiomyolipomas. Hypertrophic cardiomyopathy can be a cause of hypertension and is associated with skin lentigenes in the very rare LEOPARD syndrome. Although scoliosis is a feature of Marfans syndrome, this condition is not associated with caf-au-lait macules or hypertension. Cushings disease can cause increased general skin pigmentation but not caf-au-lait macules.

43. Why can trinucleotide repeat disorders become worse in successive generations? Modifying genes exacerbate the phenotype The phenotype is worse if the expansion is inherited by a male There is ascertainment bias with younger family members diagnosed earlier There is variable gene penetrance from generation to generation The repeat can expand from one generation to the next

Your answer

Anticipation is the phenomenon in which the age of onset of a disorder is reduced or its severity increases in successive generations. Anticipation is due to an expansion in triplet repeat size: the larger the repeat, the more unstable it is. Below a critical threshold number of repeats, the expansion will be stable and non-pathogenic (eg below 35 repeats in Huntingtons disease). Genetic diseases caused by abnormal triplet repeat expansion include Huntingtons disease, myotonic dystrophy, fragile X, Friedreichs ataxia, spinocerebellar ataxia and Kennedys disease. Although there is a general correlation with expansion size and severity of phenotype, this cannot be used to accurately predict the severity on an individual basis. Anticipation is more likely to occur in myotonic dystrophy if the expansion is maternally inherited, while in anticipation is more likely to occur in Huntingtons disease if the expansion is paternally inherited. Modifying genes and variable penetrance may account for some intrafamilial variation but would not explain the increasing severity with successive generations. The phenotype can be worse in males for X-linked trinucleotide repeat disorders such as Fragile X but is not true for autosomal trinucleotide repeat disorders. Before the molecular mechanism was understood, ascertainment bias was a seriously considered alternative explanation and it can still be a contributing factor, eg a person is more likely to be diagnosed earlier with Huntingtons disease if there is a known family history.

44. A 27-year-old woman presents with worsening back pain. As a child, she and her sister had several admissions to hospital with bone fractures following minor trauma and she has recently developed bilateral hearing loss. Apart from some teeth discoloration and mild joint laxity, examination was normal. A vertebral Xray showed partial collapse of L3. What is the most likely diagnosis? Osteogenesis imperfecta Your answer Early-onset osteoporosis EhlersDanlos syndrome Malignant bone metastases Multiple myeloma Osteogenesis imperfecta is a dominantly inherited disorder of collagen, and this woman most probably has the type 1 (least severe) form. Type 2 is lethal in utero or shortly after birth and type 3 is the severe form where affected individuals have hundreds of fractures and usually become wheelchair-bound. Clinical features include blue sclerae (not always present, as in this case), early-onset deafness and dentinogenesis imperfecta. EhlersDanlos syndrome is another collagenopathy. The classical type is typically associated with skin laxity and joint hypermobility but not with susceptibility to bone fractures. The other conditions should be considered and excluded. However, none would explain her previous history of bone fractures, teeth discoloration or hearing loss.

45. An 18-year-old army recruit undergoes preliminary health screening and is found to have a haemoglobin of 11.5 mg/dl (13-17). Spherocytes are present in the peripheral blood film. Investigation of his siblings reveals that one of his two brothers also has spherocytic anaemia. A defect in which of the following is most frequently responsible for this condition? Actin Ankyrin Glucose-6-phosphate dehydrogenase Protein 4.1 Spectrin

Your answer

The diagnosis is hereditary spherocytosis, the most frequent cause of which is a mutation in the spectrin gene. Spectrin is a component of the red cell membrane, as are actin, ankyrin and protein 4.1, mutations in all of which are less frequently responsible for the condition. Glucose-6-phosphate dehydrogenase deficiency causes haemolysis when affected individuals are exposed to certain drugs.

46. A couple attends genetic screening for an inherited condition that has been observed in the husbands family. More severe cases of so-called anticipation have been observed. What is the most likely condition? Achondroplasia Haemophilia B Marfans syndrome Myotonic dystrophy Polycystic kidney disease

Your answer

Anticipation is the tendency for a genetic disorder to become more severe and present at an earlier age in successive generations. It is usually the result of an unstable triplet repeat expansion in a gene and can show parent of origin effect. Examples of genetic disorders that show anticipation are fragile-X syndrome, Huntingtons disease, myotonic dystrophy (MD) and some of the spinocerebellar ataxias. All these conditions are caused by the expansion of a triplet repeat expansion within the gene. This repeat can undergo expansion during meiosis such that the children of an affected individual tend to inherit a larger expansion that results in more severe disease. Myotonic dystrophy is an autosomal dominant disorder caused by the expansion of a cytosinethymineguanine (CTG) repeat that lies at the 3' end of the dystrophia myotonicaprotein kinase (DMPK) gene on 19q13.3. Normal individuals have fewer than 35 CTG repeats. Affected individuals with MD have more than 50 CTG repeats. A CTG expansion of 5080 repeats is associated with early-onset cataracts. Affected individuals with

classical MD have larger CTG expansions. The most severe form of MD is congenital MD, which presents at birth with intrauterine growth retardation, severe hypotonia, muscle weakness and feeding difficulties. Children with congenital MD have developmental delay and learning difficulties and develop myotonia in their teens. Affected individuals with congenital MD have very large CTG expansions with 5002000 repeats. Expansions of this size are almost always maternally transmitted.

47. A 70-year-old Irish man is diagnosed with haemochromatosis. Subsequently, his son is also diagnosed with the condition. Both are homozygous for the common Northern European mutation. What is the most likely explanation? Autosomal-dominant inheritance Mitochondrial inheritance Non-paternity Pseudo-dominant inheritance Your answer X-linked inheritance

Haemochromatosis is an autosomal-recessive condition. However, the carrier frequency in northern Europeans is high (1 in 10); in this case the son must have inherited one mutant allele from his father and one mutant allele from his mother who must be a carrier (she may even be homozygous as women in particular are often asymptomatic). In this way, although it appears to be dominantly inherited, it is in fact a recessive condition that has been inherited in a pseudo-dominant manner. Pseudo-dominant inheritance is a feature of diseases with a high carrier frequency or consanguineous families. Both mitochondrial and X-linked inheritance do not exhibit malemale transmission and non-paternity does not explain the inheritance pattern.

48. A patient presents with distal weakness and muscle wasting. Myotonic dystrophy is confirmed by which investigation? Nerve conduction studies CT scan ECG Muscle biopsy Genetic testing

Your answer

Patients with myotonic dystrophy present with distal weakness, although proximal weakness may occur late in the course of the illness. The diagnosis is usually based on the characteristic facial features, distal weakness and wasting and the presence of grip and percussion myotonia and is confirmed by genetic testing for the characteristic expansion of the cytosinethymineguanine (CTG) triplet repeats. The condition involves skeletal, cardiac and smooth muscle. There are no distinctive pathological features on muscle biopsy and genetic testing is usually undertaken to confirm the diagnosis.

49. A 35-year-old man presents with a one-year history of choreiform movements, personality changes and mild memory loss. His father died with similar problems at the age of 50. What is the most likely diagnosis? Alzheimers disease CreutzfeldtJakob disease HallervordenSpatz disease Huntingtons disease Wilsons disease

Your answer

The most likely diagnosis in this patient is Huntingtons disease (HD)or Huntingtons chorea. This is an autosomal dominant disorder that usually presents in the third or fourth decade of life with personality change, dementia and chorea. It is a progressive neurodegenerative disorder leading to death about 15 years after onset. It is caused by the expansion of a cytosine-adenine-guanine (CAG) triplet repeat in the HD gene on 4p16. Normal repeat numbers are 935 and affected individuals have 36 repeats. Patients with Alzheimers disease usually present after the age of 50 years with slowly progressive dementia. Chorea is not a feature of this condition. Patients with CreutzfeldJakob disease (CJD) present with progressive dementia and usually die within 2 years of onset of the disease. Only a small proportion of patients with Alzheimers and CJD have familial disease and familial forms are inherited in an autosomal dominant manner. HallervordenSpatz disease is an autosomal recessive neurodegenerative disorder that usually presents in childhood or adolescence. It is characterised by pyramidal and

extrapyramidal signs, dementia, optic atrophy and the eye-of-the tiger sign on magnetic resonance imaging (MRI) scan of the brain due to the deposition of iron in the basal ganglia. Wilsons disease is also an autosomal recessive disorder. Most adult patients with Wilsons disease present with a movement disorder, personality changes and a Kayser Fleischer ring on clinical or slit-lamp examination.

50. A 40-year-old man comes to see you because he is worried about his family history of Huntingtons disease. His 45-year-old sister is known to be affected and has been given a molecular diagnosis, but neither parent is affected and both have had a normal gene test. What is the most likely reason for this inheritance pattern? Anticipation A new mutation in the sister Non-paternity Your answer Females are more often affected Non-penetrance in the parents

Huntingtons disease is an autosomal-dominant neurodegenerative condition caused by a trinucleotide repeat expansion, and both sexes are equally affected. Less than 1% of cases are due to new mutations and they are virtually all due to the same abnormal expansion. It is highly penetrant and onset is typically in middle life. The expansion is more unstable if transmitted through the paternal line, leading to a younger age of onset in the subsequent generation (anticipation). However, as the father does not carry the expansion this does not explain the situation in this family. Non-paternity would therefore have to be seriously considered. Of course, the situation would have to be handled very delicately.

51. Which one of the following statements BEST describes a patient with Wilsons disease? The primary defect is believed to be enhanced intestinal absorption of copper An alternative diagnosis should be considered if chorea occurs with no evidence of Kayser-Fleischer rings Chronic liver disease and autoimmune haemolytic anaemia are recognised features Raised serum copper levels evident at birth Siblings with biochemical evidence of the disease are treated only when they become symptomatic

Your answer

Wilsons disease is an autosomal recessive disease with a prevalence of 1 in 30,000. Its clinical and pathological manifestation results from excessive accumulation of copper in many tissues including the brain, liver, cornea and kidneys. Impaired biliary copper excretion rather than enhanced absorption is the cause of copper accumulation. Neurological manifestations typically appear between the ages of 12 and 30 years and are almost invariably accompanied by the presence of Kayser-Fleischer rings. The amount of copper in the body at birth is normal. Evidence of haemolysis in patients with chronic liver disease represents a clue to the diagnosis of Wilsons disease. The haemolysis is not immune mediated. Asymptomatic siblings that demonstrate biochemical evidence of the disease should receive treatment.

52. A 16-year-old girl presents with primary amenorrhoea. On examination, her height is 145 cm and weight 45 kg. What is the most likely diagnosis? Crohns disease Cystic fibrosis

McCuneAlbright syndrome Iron deficiency anaemia Turners syndrome

Your answer

Crohns disease and cystic fibrosis are associated with slowing of growth but not primary amenorrhoea. In polyostotic fibrous dysplasia (McCuneAlbright syndrome), precocious puberty causes premature closure of the epiphyses and short stature but menstruation is not affected. Chromosomal analysis will establish the diagnosis of true Turners syndrome (45 XO). Mosaic forms of Turners syndrome may not have these features.

53. Which of the following is a feature of restriction fragment length polymorphisms (RFLPs)? They utilise restriction exonucleases They are infrequently used in linkage analysis They may be used to diagnose Huntingtons disease They use Western blotting technique They are used in linkage which involves a difference of more than 1 million base pairs of DNA RFLPs may be used to diagnose Huntingtons disease. Enzymes from bacteria called restriction endonucleases are used in RFLPs. These are known to cleave at specific sites, resulting in specific fragments of the DNA material being analysed. The relative position of different genes on a chromosome is called linkage. By using RFLPs, a linkage map may be created when the genes are too close to be seen on microscopy. Tracking of the disease gene through successive generations may be done with RFLPs. Southern blotting is the technique used in RFLP analysis. A difference of more than a million base pairs of DNA would be detectable by microscopy. For differences less than this, RFLPs will be useful. Your answer

54. A 30-year-old man is found to have 3 adenomatous polyps in the sigmoid colon at colonoscopy. He mentions that his father died at 45 with colon cancer, his paternal aunt was treated for rectal cancer at 45 and his paternal grandfather was treated for colon cancer at 50. What is the most likely diagnosis? Familial adenomatous polyposis (FAP) Cowden syndrome

Gardner syndrome Hereditary non-polyposis colon cancer (HNPCC) PeutzJeghers syndrome

Your answer

This mans family history fulfils the Amsterdam criteria for the diagnosis of hereditary non-polyposis colon cancer (HNPCC). According to these criteria, the diagnosis of HNPCC can be made in families with three or more affected individuals with colorectal cancer where one affected individual is a first degree relative (sibling, parent or child) of the other two, at least one affected individual is diagnosed before the age of 50 years, affected individuals are present in at least two generations and familial adenomatous polyposis (FAP) has been excluded. The Amsterdam criteria have also been modified for use in smaller families and to take into account that women with HNPCC are at greater risk of endometrial cancer than colorectal cancer. Adenomatous colonic polyps can be seen in both FAP and HNPCC. However, in FAP there are usually numerous polyps (more than 100 and often more than 1000) with a predominantly left-sided distribution, whereas in HNPCC there are only a small number of polyps with a predominantly right-sided distribution. Gardner syndrome is characterised by adenomatous polyposis of the colon, benign osteomas of the skull and facial bones, epidermoid cysts, dental abnormalities (odontomas, supernumerary and impacted teeth) and desmoid and other tumours. Gardner syndrome and FAP are both caused by mutations in the adenomatosis polyposis coli (APC) gene on 5q22. Small and large bowel polyps are an important feature of Cowden and PeutzJeghers syndromes but the polyps are usually hamartomatous.

55. What is the main feature of DNA sequence polymorphisms that differentiates them from mutations? They are common in the population Your answer They often cause serious medical conditions They usually interfere with normal gene function They are not found in certain ethnic groups

They are evenly spread throughout all genes

A polymorphism is a DNA sequence variant that is common in the population, whereas a mutation is a change in a DNA sequence away from normal that results in an abnormal rare variant. However, these definitions are not absolute. The usual cut-off point between a mutation and a polymorphism is 1%. Therefore, if the DNA sequence variant has a frequency of 1% or higher, it is classed as a polymorphism, whereas it is regarded as a mutation if the frequency is lower than 1%. Polymorphic sequence variants are found in all populations and usually do not cause clinically serious diseases. Some genes are more polymorphic than others. Many polymorphisms are found outside of genes and have no effect on gene function. Others may be found within genes, and modify gene function to influence characteristics such as height and hair colour rather than being pathogenic. However, polymorphic sequence variation does affect disease susceptibility and can also influence drug responses.

56. A 20-year-old woman, who was prescribed the oral contraceptive pill a week earlier, develops central abdominal pain, vomiting and weakness in both lower limbs. Blood tests show an elevated white cell count. What is the most probable diagnosis? Guillain-Barr syndrome Polyarteritis nodosa Sarcoidosis Diabetic ketoacidosis Acute intermittent porphyria

Your answer

Acute intermittent porphyria (AIP) is the most common type of acute porphyria. It is five times more common in females and presents between 15 and 30 years of age. The oral contraceptive pill can precipitate an acute attack in AIP. GuillainBarr syndrome commonly presents with headache, vomiting, pyrexia, back and limb pain followed by paralysis. It usually follows 1 4 weeks after a respiratory tract infection or diarrhoea. Renal functions are affected in over 75% of patients with polyarteritis nodosa. Fever, malaise, weight loss and arthralgia are common symptoms in this condition. Abdominal pain may occur due to infarction or malabsorption caused by chronic ischaemia. In sarcoidosis, hypercalcaemia and hypercalciuria are common while abdominal pain is uncommon. A 2 to 3-day history of gradual deterioration with dehydration, acidosis and coma characterises diabetic ketoacidosis.

57. A young pregnant girl would like to know the risk of having a child with genetic abnormalities. Her father and two brothers are affected by haemophilia, which is inherited as an X-linked disease. She is herself completely asymptomatic. She knows from her last ultrasound test that her baby is a boy. What is the chance for her son to be genetically affected by the same condition? 1 in 2 1 in 4 1 in 6 1 in 8 1 in 16 Your answer

Males are hemizygous, receiving their only X chromosome from their mother. Females are heterozygous, inheriting X chromosomes from both parents. If a female has a defective gene on one of her two X chromosomes, she will be protected from its effects by the normal gene on her second X chromosome. If a male has a mutant X and a normal Y chromosome, he will be affected by a X-linked disease. A son, whose mother has two normal alleles, will not be affected by haemophilia even if the father has the disease and the defective gene. A daughter of the same parents will be a heterozygous carrier. A heterozygous carrier mother and a normal father pass the gene for haemophilia on to possibly one-half of their children. Half the daughters will be carriers and half the sons will be haemophilic. The rest of the siblings will be normal. Daughters, as long as one parent is genotypically normal, can only be carriers. The normal gene on the second X chromosome counteracts the defect, and the daughters do not suffer from the trait. If a son receives the defective gene from his mother, he will be haemophilic because the Y chromosome cannot counteract the defective gene located on his X chromosome.

58. A man in his mid-60s is referred to you because he is worried about his family history of ischaemic heart disease. His father was a non-smoker and died of a myocardial infarction aged 39 years. His maternal grandfather and a paternal uncle both had myocardial infarcts in their 40s. What is his history most suggestive of? Hyperhomocysteinaemia Homocystinuria Familial hypercholesterolaemia Your answer

Factor V Leiden deficiency Haemochromatosis Familial hypercholesterolaemia affects around 1 in 500 of the population and is associated with a significantly increased risk of cardiovascular disease. Although there is epidemiological evidence that elevated plasma homocysteine levels are associated with cardiovascular disease, it is unlikely to be responsible for the strong family history in the question. Homocysteinuria is an autosomal-recessive inborn error of methionine metabolism and is associated with a greatly increased incidence of atheroma. Affected individuals often have a marfanoid habitus and downward lens dislocation is also a well-recognised feature. However, the autosomal-recessive inheritance pattern would not fit with this family history. Neither Factor V Leiden deficiency nor haemochromatosis are associated with an increased risk of cardiovascular disease, although cardiomyopathy is a feature of haemochromatosis.

59. A young man with severe learning difficulties and congenital heart disease is referred to you for a cardiac assessment. He is accompanied by his carer who says he has a chromosome abnormality. What type of abnormality is most likely to cause such a severe phenotype? Balanced autosomal translocation Unbalanced autosomal translocation Your answer Pericentric inversion Paracentric inversion Sex chromosome aneuploidy As a rule, the clinical effects of a chromosome abnormality reflect the amount of

imbalance of genetic material. For example, all autosomal monosomies and most autosomal trisomies are incompatible with life, the exceptions being trisomy 13 (Pataus syndrome), trisomy 18 (Edwards syndrome) and trisomy 21 (Downs syndrome): only the last of these carries a reasonable life expectancy. Inversions (where a piece of a chromosome is swapped around itself) often do not have a clinical phenotype but are commonly found as an incidental finding. Occasionally the inversion breakpoint is across a critical gene and causes a clinical disorder. Balanced autosomal translocations are also not normally associated with morbidity. These may only come to light when offspring are born with an unbalanced autosomal translocation that results in an abnormal copy number for one or more chromosome regions (eg trisomic for one region and monosomic for another). Such chromosome abnormalities are generally associated with congenital abnormalities, relatively short stature and intellectual impairment, although the exact phenotype can vary widely. Sex chromosome aneuploidies are associated with comparatively less-severe phenotypes, eg Klinefelters syndrome (XXY) and Turners syndrome (XO).

60. A man who has common variable immunodeficiency would like to start a family. His partner does not have the disease. What is the percentage that his children will inherit his disease? 100% <5% 25% 50% 0%

Your answer

Common variable immunodeficiency is an autosomal recessive disorder, with a prevalence of around 1 : 50,000. All children of the patient will carry at least one gene for common variable immunodeficiency, but the chance of his partner carrying one copy of the gene is low. Patients commonly present with a history of recurrent infections and often have associated autoimmune phenomena such as rheumatoid arthritis, vitiligo, haemolytic anaemia or neutropenia. Patients have an increased risk of B-cell lymphoma. Twenty-year survival rate is around 64% for man patients and 67% for female patients.

61. A 25-year-old woman is referred to you for treatment of her asthma. She is otherwise well and there is no significant previous medical history. During the consultation it transpires that her sister died of cystic fibrosis and she is worried about having a child affected with the same disease. Her chest X-ray is normal. Assuming a population carrier frequency of 1 in 25, what is the chance of her having an affected child? 1 in 10 1 in 50 1 in 100 1 in 150 Your answer 1 in 200 Your patient would have a 2 in 3 chance of being a carrier, as she is not affected herself (the history of asthma is coincidental). Her partner would have a 1 in 25 chance of being a carrier. The chance of having an affected child if both are carriers is 1 in 4. Therefore the overall chance is 2/3 1/25 1/4 = 1/150. The commonest mistake (which also applies to other autosomal-recessive diseases) is to assume that her chance of being a carrier is 1 in 2, on the premise that there is a 1 in 4 chance of being affected, 1 in 4 of not being a carrier and a 1 in 2 chance of being a carrier. As she is not affected, the chance of being a carrier is in fact 2 in 3 and the chance of not being a carrier is 1 in 3.

62. A 25-year-old accountant is admitted to hospital with severe abdominal pain, vomiting and postural hypotension. She has had similar attacks in the past. A mid-stream urine sample shows the presence of high levels of aminolaevulinic acid (ALA) and porphobilinogen (PBG). What is the most likely diagnosis?

Hereditary coproporphyria Porphyria cutanea tarda Acute intermittent porphyria Erythropoietic protoporphyria Variegate porphyria

Your answer

Acute intermittent porphyria (AIP) presents with gastrointestinal and neurological symptoms. Central abdominal pain and bilious vomiting are characteristic. AIP occurs due to the absence of porphobilinogen (PBG) deaminase. This leads to elevated levels of 8ALA and PBG. Attacks are intermittent, more common in women and may be precipitated by a number of drugs. There are no skin manifestations. Both variegate porphyria and hereditary coproporphyria are associated with photosensitive blistering skin lesions. Erythropoietic protoporphyria and porphyria cutanea tarda are cutaneous porphyrias. In the majority of these patients subepidermal bullae and hypertrichosis develop. In erythropoietic protoporphyria, the patient develops a burning sensation affecting light-exposed parts of the skin. Urinary PBG and ALA levels are normal in both these conditions.

63. A woman has von Willebrands disease and so does her partner. They wish to have children and seek genetic counselling. How would the risk of disease transmission to her offspring be best described? All the children will have the disease All the children will be carriers Half the children will be carriers Three-quarters of the children will have the disease All the sons will be affected

Your answer

Von Willebrands is autosomal dominant. If both parents have the disease, then threequarters of their offspring will have the disease (on the assumption that both parents are heterozygote in the exam, this is a fair assumption). There is no carrier state and, as it is an autosomal disease, there is no sex difference. 64. Patients with xeroderma pigmentosum have a high risk of developing skin cancer. What kind of genetic deficiency do those patients have? Nucleotide excision repair Protein kinase Base excision repair Mismatch repair Ligase Your answer

Xeroderma pigmentosum is an inherited skin disorder characterised by photosensitivity with severe sunburn in infancy, the development of numerous pigmented spots resembling freckles, larger atrophic lesions associated with telangiectasis, and multiple solar keratoses. Transmitted in an autosomal recessive manner, xeroderma pigmentosa involves a defect in nucleotide excision repair (NER), leading to deficient repair of DNA damaged by UV radiation and chromosome breakage. Individuals with this disease develop multiple malignant cutaneous neoplasms at an early age, and may suffer from severe ophthalmic and neurological abnormalities.

65. In Duchennes muscular dystrophy, which of the following statements applies? Serum creatinine kinase is elevated in 30% of cases Exon deletion or duplication in the dystrophin gene occurs in 60% of patients Prenatal diagnosis involves analysis of restriction fragment length polymorphisms (RFLPs) The genetic defect affects mainly skeletal muscle 50% of male fetuses are affected

Your answer

Duchennes muscular dystrophy is an X-linked recessive disorder in which affected boys develop progressive weakness of the limb-girdle muscles. Most muscular tissues, including cardiac tissues, are involved. An abnormally high creatinine kinase level is found in all these patients. Since 60% of patients have an exon deletion or duplication in the dystrophin gene, this can be tested directly without the need for analysis of RFLPs.