CHAPTER 6: Developmental Genetics
1 The combination of macrocephaly, odontogenic keratocysts, and basal cell carcinomas occurs in Gorlin (basal cell nevoid carcinoma) syndrome. This condition should be in the differential diagnosis of a child with macrocephaly, with appropriate exploration of the family history. It is understandable that hydrocephalus would be the main concern, but true hydrocephalus is unusual in Gorlin syndrome.
2 The child’s father is an obligate carrier for the PTCH gene mutation causing Gorlin syndrome in the family. He should be screened regularly (at least annually) by radiography for odontogenic keratocysts, and be under regular surveillance by a dermatologist for basal cell carcinomas. PTCH gene mutation analysis is possible for any affected family member.
1 The two most likely causes of sex reversal in a young ‘girl’ are androgen insensitivity syndrome (AIS), which is X-linked and results from mutations in the androgen receptor gene, and mutations in the SRY gene on the Y chromosome.
2 Mutation analysis in both the androgen receptor and SRY genes can be performed to determine the genetic basis of the sex reversal. It is very important to investigate and locate, if present, remnants of gonadal tissue because this will have to be removed to avoid the risk of malignant change. Because of this, the parents should be given a full explanation, but the phenotypic sex of the child should be affirmed as female.
CHAPTER 7: Patterns of Inheritance
1 It is possible that the problems described in family members are unrelated, but this is unlikely. If the condition has passed from the grandfather, mitochondrial inheritance is very unlikely. The condition is either autosomal dominant with variability, or X-linked.
2 The spinocerebellar ataxias are a genetically heterogeneous group of conditions that usually follow autosomal dominant inheritance and could present in this way. A form of hereditary spastic paraparesis is possible, also genetically heterogeneous and usually after autosomal dominant inheritance, although recessive and X-linked forms are described. Apart from these, X-linked adrenoleukodystrophy must be considered, especially because the man has signs of cognitive and behavioral problems. This is very important, not only because it can present early in life but also because of the potential for adrenal insufficiency.
1 The information may be correct but is probably not and other possibilities must be explained to them.
2 Most forms of osteogenesis imperfecta (brittle bone disease) follow autosomal dominant inheritance. Sibling recurrence, when neither parent has signs or symptoms, can be explained by somatic and/or germline mosaicism in one of the parents. The risk to the offspring of those affected would then be 50% (i.e., high). In this case history, the possibility of a non-genetic diagnosis must be considered, namely non-accidental injury. It is therefore important to try to confirm the diagnosis.
CHAPTER 8: Mathematical and Population Genetics
1 Clearly, it is essential to know whether the condition in question has ever knowingly occurred in the families of either of the two consultands. If this had occurred, it would potentially modify the carrier risk for one of the consultands regardless of the frequency of the disease in the population.
.1 From the figures given, four cases in the town appear to be new mutations, i.e., four new mutations per 100,000 genes inherited. The mutation rate is therefore 1 per 25,000 gametes.
2 The population sample is small and may not therefore be representative of the larger, wider population. For example, if there is a bias toward an older, retired population, the reproducing subpopulation may be smaller and the figures distorted by the migration of younger people away from the town. In addition, the four ‘new mutation’ cases should be verified by proper examination of the parents.
CHAPTER 9: Polygenic and Multifactorial Inheritance
1 Testing for factor V Leiden and the prothrombin G20210A variant is appropriate. A positive result would provide a more accurate risk of her developing thromboembolism and would inform her choice of contraception. Heterozygosity for factor V Leiden or the prothrombin G20210A variant would increase her risk by four- to fivefold. Homozygosity or compound heterozygosity would increase her risk by up to 80-fold.
1 The proband might have type 1 diabetes (T1DM), type 2 diabetes (T2DM), or maturity-onset diabetes of the young (MODY). Because both have normal hearing, a diagnosis of maternally inherited diabetes and deafness (MIDD) is unlikely. T1DM and T2DM show multifactorial inheritance with environmental factors playing a role in addition to predisposing genetic susceptibility factors. MODY shows autosomal dominant inheritance.
2 The brother’s risk of developing diabetes is 6%, 35%, or 50%, respectively. If his sister is found to have a mutation in one of the genes causing MODY, then he could have predictive genetic testing. A negative test would reduce his risk to that of the population. A positive test would allow regular monitoring in order to make an early diagnosis of diabetes and avoid diabetic complications from long-standing undiagnosed diabetes.
CHAPTER 10: Hemoglobin and the Hemoglobinopathies
1 The ethnic origin of the couple and the limited information should suggest the possibility of a hematological disorder. α-Thalassemia is the likely cause of stillbirth, hydrops being secondary to heart failure, which in turn is secondary to anemia. Rhesus isoimmunization and glucose-6-phosphate dehydrogenase deficiency are other possibilities. Severe forms of congenital heart disease are frequently associated with hydrops, but the chance of a sibling recurrence (which occurred in the case history) is low. However, there are many other causes of hydrops and these would need to be considered. Among those that are genetic with a chance of recurrence are lethal forms of rare skeletal dysplasias and a wide range of metabolic disease.
2 A full blood count, blood groups, Hb electrophoresis, and maternal autoantibody and glucose-6-phosphate dehydrogenase deficiency screens should be performed for the couple. DNA analysis may detect the common mutation seen in Southeast Asia, which would then make it possible to offer genetic prenatal diagnosis by chorionic villus sampling. If no disorder is identified by these investigations it is unlikely that further diagnostic progress will be made unless the couple has another affected pregnancy that can be fully investigated by examination of the fetus.
1 This presentation is consistent with acute intermittent porphyria and hemolytic uremic syndrome. However, the ethnic origin should suggest the possibility of sickle cell disease. The contents of the dark urine, and specific tests for porphyria, will help to differentiate these, and a sickle cell test should be performed.
2 If the diagnosis is sickle cell disease there are various agents that can be tried to reduce the frequency of sickling crises—hydroxyurea in particular. Prophylactic penicillin is important for reducing the risk of serious pneumococcal infections, and the family should be offered genetic counseling and cascade screening of relatives.
CHAPTER 11: Biochemical Genetics
1 Hypoglycemia can be part of severe illness in young children, but in this case the intercurrent problem appears relatively minor, suggesting that the child’s metabolic capacity to cope with stress is compromised. This history should prompt investigations for a possible inborn error of metabolism and, if a diagnosis is made, the younger sibling should be tested.
1 If there is a family history of similar symptoms, it might demonstrate matrilinear inheritance with all the offspring of affected males being normal. If this person is the only affected individual, a family history will not be informative with respect to the diagnosis.
2 All causes of myopathy need to be considered, but the combination of features is suggestive of a mitochondrial cytopathy. This would explain the muscular symptoms, ptosis, and hearing impairment—and there might also be evidence of a cardiomyopathy, neurological disturbance, retinitis pigmentosa, and diabetes mellitus. Mitochondrial DNA analysis on peripheral lymphocytes might identify a mutation, although a negative result would not rule out the diagnosis. A muscle biopsy might show ragged red fibers, and DNA analysis on this tissue might be more informative than lymphocytes.
CHAPTER 13: Immunogenetics
1 The nature of his grandfather’s symptoms are rather non-specific—back pain and arthritis are both very common in the general population. However, it is certainly possible that he also had ankylosing spondylitis, a form of enthesitis (inflammation at the site of insertion of a ligament or tendon into bone) with involvement of synovial joints, as the heritability is greater than 90%.
2 About 95% of patients with ankylosing spondylitis are positive for the HLA-B27 antigen; however, in the general population this test has only a low positive predictive value. His children have a 50% chance of being HLA-B27 positive; if positive, the risk of developing clinical ankylosing spondylitis is about 9%; if negative, the risk is less than 1%.
CHAPTER 14: Cancer Genetics
1 The family history should first of all be confirmed with the consent of the affected individuals. If the thyroid cancer in the cousin was papillary in type, and the polyps in her father hamartomatous, the pattern would be very suspicious for Cowden disease. This is also known as multiple hamartoma syndrome, which is autosomal dominant and often the result of mutations in PTEN; the risk of breast cancer is approximately 50% in females.
1 If the BRCA2 mutation has not been confirmed in another family member or by testing another sample from the deceased cousin (e.g., a tissue section embedded in paraffin), the possibility of a sample mix-up in the research laboratory cannot be excluded. If, however, the uncle tests positive for the mutation, the consultand’s mother is a phenocopy. Alternatively the mutation may have been inherited from the cousin’s mother.
CHAPTER 15: Genetic Factors in Common Diseases
1 Generally, the risk of epilepsy to first-degree relatives is around 4%. However, mother and daughter are affected here, which suggests the possibility of a mendelian form of epilepsy. Furthermore, it seems that both have an abnormal finding on brain imaging and the mother’s computed tomograms should be located and reviewed. At this stage, an explanation of both autosomal dominant and X-linked inheritance should be given, as well as the possibility that the two cases of epilepsy are coincidental.
2 The condition that the mother’s doctors mentioned would almost certainly have been tuberous sclerosis (TS), which follows autosomal dominant inheritance. Further evaluation of both mother and daughter looking for clinical features of TS might be indicated and genetic testing is available. However, the nodules on the lateral ventricle walls may be pathognomonic of bilateral periventricular nodular heterotopia (BPVNH) and the images should be reviewed by someone who can recognize this. BPVNH is an abnormality of neuronal migration and is inherited as an X-linked dominant condition, caused by mutations in the filamin-1 (FLNA) gene. Testing is available. In general, mendelian forms of epilepsy are rare.
1 Not necessarily. Many people with glucokinase gene mutations are asymptomatic and their mild hyperglycemia is detected only upon screening (routine medicals, during pregnancy or intercurrent illness). Gestational diabetes in the father’s sister suggests that the mutation could have been inherited from his side of the family.
2 Identification of a glucokinase gene is ‘good news’ because the mild hyperglycemia is likely to be stable throughout life, treated by diet alone (except during pregnancy) and unlikely to result in diabetic complications. Cascade testing can be offered to other relatives. If the mutation has been inherited from the father, his sister and her child may be tested. The sister might avoid the anxiety of having a young child diagnosed with unexplained hyperglycemia.
CHAPTER 16: Congenital Abnormalities and Dysmorphic Syndromes
1 This is not an unusual scenario. The karyotype on amniocentesis was normal and polyhydramnios suggests the possibility of a gastrointestinal obstruction such as esophageal atresia. The abnormalities are more likely to represent an ‘association’ rather than a syndrome or mendelian condition. The empiric recurrence risk is low, and all that can be offered is ultrasonography in subsequent pregnancies.
2 A fetal autopsy is highly desirable in this situation to know the full extent of internal organ anomalies. A repeat karyotype on fetal skin might have shown something that was not detected on amniocentesis, and DNA should be stored for possible future use. Maternal diabetes should be excluded. As a last resort, the parents’ chromosomes could be tested, including telomere screens to look for the possibility of a cryptic translocation.
1 Isolated, non-syndromic cleft palate is statistically the most likely diagnosis, but the mild short stature might be significant. Syndromic possibilities include spondyloepiphyseal dysplasia congenita (SEDC)—although there are many rare syndromes with more severe short stature and other features.
2 The short stature appears mild; it is, therefore, important to try to determine whether this might be familial—the parents need to be assessed. Follow-up of the baby is indicated, including a radiological skeletal survey to see whether there is an identifiable skeletal dysplasia. SEDC may be accompanied by myopia and sensorineural hearing impairment; therefore hearing and vision assessment is important. However, the child has cleft palate and is at risk of conductive hearing problems as a result. The cleft palate team needs to be involved from the beginning.
CHAPTER 17: Genetic Counseling
1 The couple is at risk of having further affected children and prenatal diagnosis can be offered. The father may have inherited the balanced translocation from one of his parents and his sister may also be a carrier. Carrier testing should be offered to his family, especially as his sister is trying to get pregnant.
2 The father’s wider family needs to be made aware of the child’s diagnosis, but have fixed misconceptions and it might be very difficult to accept that the child’s problems have their origin on their side of the family. There is a severe communication problem but a way needs to be found to inform the father’s wider family of the genetic risk. It might be necessary to involve their general practitioners.
1 There is now no need for the woman to undergo an invasive prenatal test in future pregnancies; this would be a waste of resources and place the pregnancy at a small but unnecessary risk of miscarriage.
2 There is the difficulty of communicating the fact that a prenatal test is not necessary, but disclosure of non-paternity may have far-reaching consequences for the marriage. The counselors do not know whether the ‘father’ suspects non-paternity, and the mother may think he is the biological father of the child.
CHAPTER 18: Chromosome Disorders
1 Head-banging is not rare in early childhood, especially in children with developmental delay, and it is not necessarily a helpful feature in making a diagnosis. However, combined with the persistently disturbed sleep pattern, the diagnosis of Smith-Magenis syndrome should be considered. These children can be quiet as babies and have congenital heart disease.
1 The previous counseling given naturally assumed the girl was pure 47,XXX. However, the subsequent course raises the possibility that she has chromosome mosaicism, and in particular she might be mosaic for Turner syndrome (45,X). A buccal smear and/or skin biopsy should be offered to look at chromosomes in a tissue other than blood. If this is normal, other causes of short stature would need to be considered.
2 If the child is indeed found to be a 45,X/47,XXX mosaic, she needs to be investigated for the complications of Turner syndrome—congenital heart disease and horseshoe kidney. In addition, her fertility is in question and she would need to be referred to a pediatric endocrinologist, who would also assess her for possible growth hormone treatment.
CHAPTER 19: Single-Gene Disorders
1 The history in the brother is consistent with his having Becker muscular dystrophy (BMD) but is also consistent with other diagnostic possibilities, e.g., limb-girdle muscular dystrophy (LGMD). These two conditions have sometimes been difficult to distinguish and the inheritance is different, with quite different implications for the woman who wishes to start a family.
2 The medical records of the affected brother should be reviewed and he should be reassessed. Thirty years ago the tests for BMD were very basic but now dystrophin gene mutation analysis is available. A muscle biopsy subjected to specific dystrophin staining may be diagnostic, but if this is negative staining techniques for different forms of LGMD are available. If one of the LGMD group, the woman can be reassured because these follow autosomal recessive inheritance. If BMD, carrier testing for the consultand would be straightforward if only a specific mutation were found in her brother.
1 The sudden, unexpected death of young adults, especially when no cause can be identified, is extremely shocking for a family. The focus of attention becomes the inherited arrhythmias and cardiomyopathies—sometimes the latter show no obvious features at post-mortem examination. All close family members are eligible for cardiac evaluation by echocardiography, ECG, and provocation tests, looking for evidence of the long QT and Brugada syndromes. Genetic testing is available but not guaranteed to identify a pathogenic mutation. Some forms of inherited arrhythmia/cardiomyopathy are amenable to prophylactic treatment; for others very little is available.
2 Management will depend on the outcome of investigations and genetic testing. However, if no specific findings are made it is very difficult to know how to advise families like this. High-intensity sports and swimming should probably be avoided in case such activity is a precipitating factor for a life-threatening arrhythmia.
CHAPTER 20: Screening for Genetic Disease
1 Mutation analysis in the fibrillin-1 gene is possible for the consultand but not guaranteed to identify a mutation even if the clinical diagnosis is confident. Linkage analysis at the fibrillin-1 locus on chromosome 15 would be possible using DNA from the consultand’s mother and inferring the haplotype of the father, whose affected status would have to be assumed. In a small family, however, linkage may be consistent with segregation of the condition by chance. Furthermore, in unusual cases Marfan syndrome is due to a mutated gene at a separate locus on chromosome 3. There are serious pitfalls to genetic testing in this situation.
2 The important life-threatening complication of Marfan syndrome is progressive aortic root dilatation carrying a risk of dissection. Those with a firm diagnosis must be followed until at least the age of 30 years. If there is doubt about the diagnosis, regular cardiac screening is probably a sensible precaution for all those at risk until their mid-twenties.
+ 5 = 90%. The specificity is the proportion of true negatives detected by the test, i.e., 99,190 (the unaffected cases who test negative)/99,190 + 760 (the unaffected cases who test positive) = 99.2%.
= 5.6%.CHAPTER 21: Prenatal Testing and Reproductive Genetics
1 The finding of mosaicism for trisomy 20 in chorionic villus tissue might have been a case of confined placental mosaicism. The latter is not a rare event for a wide variety of chromosome aberrations but, as long as it is confined, there are no serious consequences for the pregnancy. The problem with going on to perform an amniocentesis is in interpretation of the result. If no abnormal cells are found, this does not completely rule out chromosome mosaicism in the fetus. If abnormal cells are found, the clinical implications are very difficult, if not impossible, to predict.
2 This case illustrates the rollercoaster of emotions and experiences that some women and couples have to cope with as a result of different forms of prenatal tests and their interpretation. In fact, trisomy 20 mosaicism is unlikely to be of great clinical significance—but it is very difficult to be sure. Renal abnormalities have been reported, and detailed fetal anomaly scanning can be offered for the remainder of the pregnancy. However, what might have been an enjoyable pregnancy will probably continue to be an anxious one.
1 In the large majority of autism cases, no specific diagnosis is reached. Chromosome analysis, including a multi-telomere screen, fragile X syndrome, a metabolic screen, and examination for neurocutaneous disorders, should all be performed.
2 This is a very difficult situation. However, there is no proof in this case that autism is X-linked, and therefore no guarantee that any daughter will be unaffected. It would, therefore, be very difficult to support this request in the United Kingdom where PGD is regulated by the Human Fertilization and Embryology Authority, and sex selection for anything other than clearly X-linked conditions is not licensed. In other countries, where these techniques are not regulated, the couple might find clinicians who acquiesce to their request.
CHAPTER 22: Risk Calculation
1 Each of the siblings of the affected aunt has a chance of being a carrier; therefore, each of the cousins has a chance of being a carrier. The chance of the couple’s first baby being affected is 
.
.2 Even though genetic studies cannot be performed, biochemical prenatal testing can be offered for their pregnancies, although biochemical tests will not reliably determine whether they are carriers. If they elect for prenatal testing, it would also be worth testing for Hunter syndrome, which can easily be confused with Hurler syndrome clinically, and is X-linked.
1 A simple Bayes’ calculation can be performed, taking into account that she has had two normal sons (Table 1). She therefore has a 
, or 20%, chance of being a carrier.
, or 20%, chance of being a carrier.2 There is a good chance of identifying the factor VIII gene mutation in either her brother or uncle if either of them is still alive. If so, it should then be possible to determine her carrier status definitively. If not, tests of factor VIII levels and factor VIII–related antigen may give a result that can modify her risk, but this is not necessarily discriminatory. DNA linkage analysis would be much more reliable, provided DNA samples are available.
| Probability | Is a Carrier | Is Not a Carrier |
|---|---|---|
| Prior |  |
 |
| Conditional (2 normal sons) |  |
1 |
| Joint |  |
 |
| Posterior |  |
