risk of miscarriage (chorionic villus sampling or amniocentesis).Clinical genetics is the medical speciality that deals with diagnosis and genetic counselling for individuals and families with, or at risk of, conditions that may have a genetic basis. Genetic disorders can affect any body system and any age group.
Examples of genetic disorders include:
• chromosomal abnormalities, e.g. Down syndrome
• single gene disorders, e.g. cystic fibrosis (CF)
• birth defects with a genetic component, e.g. cleft lip and palate.
Clinical genetics services in the UK are based at 23 regional genetics centres consisting of a clinical team of doctors and genetic counsellors and the genetics laboratories (for molecular and cytogenetic testing). Clinical genetics may be taught as part of the paediatrics rotation. Clinical geneticists usually visit district general hospitals several times a month. It should be possible to arrange to sit in on clinics. You may need to telephone the department to arrange this in advance.
Medical students can often choose to do a placement in clinical genetics such as a student selected component or special studies module. This involves a longer placement of several weeks in the department and provides an opportunity to attend a range of different clinics and clinical meetings and sometimes organize a project.
Clinical geneticists see a wide range of cases, some relatively common and some very rare. It will not be possible to see everything during a short attachment. Try to see a range of cases such as the following:
Seeing pregnant couples who are concerned about a genetic disease either due to family history or abnormal results of screening tests/scans. The focus is on assessing the risk, seeing if testing is available during pregnancy, and helping couples decide whether they would like invasive testing (or non-invasive prenatal testing/diagnosis if available) and how they would use the information.
Seeing babies and children who are suspected to have a genetic problem, e.g. due to a congenital anomaly or developmental delay. A detailed family history, pregnancy and birth history, and developmental history will be taken, and a detailed examination made. Clinical photographs are often taken to aid further discussion in the department. The focus is on trying to make a diagnosis, as this gives information about prognosis, potential complications, and recurrence risk.
E.g. CF, hereditary haemochromatosis, Marfan syndrome, NF1, and Duchenne muscular dystrophy. The focus may be on explaining the diagnosis and prognosis, implications for the wider family, or reproductive options.
Common cancer predisposition syndromes such as hereditary breast and ovarian cancer (BRCA1 and BRCA2 genes) or Lynch syndrome (hereditary non-polyposis colorectal cancer (HNPCC)).
E.g. Down syndrome, Klinefelter syndrome, Turner syndrome, chromosomal translocation (may be found during investigation of recurrent miscarriage), microdeletions, or microduplications.
Clinical genetics is not a procedure-based speciality, although you may need to take blood.
Clinical genetics is mainly led by consultants and genetic counsellors (nurses or science graduates who have had specialist training in genetic counselling usually through a master’s degree). As a student, you will spend most of the time observing. You will need to practise taking family histories and drawing accurate pedigrees. You will need to be able to identify common inheritance patterns in families (e.g. autosomal dominant (AD), autosomal recessive (AD), X-linked), and explain them to patients in straightforward language. You should think about the communication skills that are very important in clinical genetics such as taking informed consent, breaking bad news, considering patient confidentiality within families, non-directional counselling (in particular about predictive testing and reproductive choices), and explaining complex information in simple language.
Common genetic conditions by specialty
• Cardiology: hypertrophic cardiomyopathy, Marfan's syndrome.
• GI: hereditary haemochromatosis.
• Neurology: Charcot–Marie–Tooth disease, Huntington disease (HD), myotonic dystrophy.
• Oncology: familial breast and ovarian cancer, familial adenomatous polyposis, Lynch syndrome (HNPCC).
• Ophthalmology: retinitis pigmentosa.
• Paediatrics: Down syndrome, developmental delay, dysmorphic features, fragile X syndrome, Duchenne muscular dystrophy.
Geneticists see a wide range of different cases and you should aim to sit in on different types of consultations as described in the overview. It will also be helpful to see families with the different inheritance patterns.
The gene which causes the disorder is encoded on an autosome (i.e. not the X or Y chromosome) and the disorder manifests in heterozygotes, i.e. when a single copy of the gene is mutated. Examples include Marfan syndrome, NF1, and HD. AD disorders are characterized by variability between and within families. The severity may be influenced by other modifier genes or environmental factors.
• Males and females are affected equally.
• Males and females can transmit the disorder.
• There is a one in two (50%) chance that the offspring in any pregnancy will inherit the mutation.
The percentage of individuals with the mutation who have clinical features of the disorder to any degree (from trivial to severe). Many AD disorders show age-dependent penetrance—the features of the disorder are not present at birth but become evident over time (e.g. HD). Some AD disorders show incomplete penetrance—meaning that not all mutation carriers develop features of the disorder over their lifetime. This can lead to a condition seeming to ‘skip a generation’ (e.g. Lynch syndrome).
Variability in the severity of the disorder in individuals with the same mutation, between and within families. Mildly affected parents should be aware of the risk of having a severely affected child.
The rate of new mutations varies considerably between disorders, e.g. up to 50% for NF1, but low in HD.
This means testing an unaffected individual who has a family history of a genetic disorder and a known mutation in the family. It is important that the individual should have genetic counselling to explain the features of the disorder, the inheritance pattern, and the pros and cons of testing. Some disorders may have screening or other treatment available (e.g. 2-yearly colonoscopy screening from age 25 in Lynch syndrome carriers, and taking aspirin decreases the risk of developing cancers), while others do not have any treatment or screening currently available (e.g. HD) so the test result would be for information only. It may affect life choices/reproductive decisions.
The gene which causes the disorder is located on an autosome (i.e. not the X or Y chromosome) and the disorder manifests when both copies of the gene are mutated, i.e. in homozygotes (two identical mutations) and compound heterozygotes (two different mutations). They include CF, sickle cell disease, and spinal muscular atrophy. Heterozygotes (carriers) do not manifest a phenotype (e.g. CF) or if they do, it is very mild compared with the disease (e.g. sickle cell trait vs sickle cell disease).
• Disease expressed only in homozygotes and compound heterozygotes.
• Parents are obligate carriers (an exception is spinal muscular atrophy—new mutation rate ~2%).
• Risk of carrier parents having an affected child is one in four (25%).
• Healthy siblings of an affected child have a two-thirds risk of being carriers.
• Risk of carrier status diminishes by half with every degree of relationship from parents of an affected child.
• All offspring of an affected individual whose partner is not a carrier are obligate carriers.
AR disorders are commoner in the offspring of consanguineous partnerships, because the parents share more of their genome than unrelated individuals. A consanguineous relationship is one between individuals who are second cousins or closer.
Population risk for carrier status can be calculated by geneticists using the Hardy–Weinberg equation. Approximate carrier frequency in the white British population = 1 in 25 for CF, and 1 in 10 for hereditary haemochromatosis.
Testing relatives of an affected individual is straightforward if the mutations are known in the affected individual. Testing an unrelated partner is usually more difficult, as recessive diseases can be caused by many different mutations within the gene. Sickle cell disease is caused by one recurrent mutation, so testing is straightforward. Spinal muscular atrophy is mainly caused by a recurrent deletion, so testing of people at population risk is possible but does not give a definite answer. CF carrier testing uses a panel of common mutations which covers ~85% of mutations in the white British population, so the testing does not give a definite answer but can give a risk estimate.
This means tracking a mutation through a family. This is often done for serious AR conditions (e.g. CF) to give information for reproductive choices. It is also especially important for balanced chromosomal translocations. It can be done for AD conditions, particularly if screening or treatment is available.
Disorders are encoded on the X chromosome. Examples include Duchenne muscular dystrophy, fragile X syndrome, and haemophilia A. An X-linked recessive disorder manifests in males who have one X chromosome but generally not in females who have two X chromosomes (one normal and one mutated copy). Some disorders almost never cause symptoms in females and in some, females have symptoms infrequently (e.g. Duchenne muscular dystrophy), whereas for others (e.g. X-linked Charcot–Marie–Tooth disease, and fragile X syndrome), manifestation is fairly common but is usually less severe than in affected males. This is called X-linked semidominant inheritance.
• No male-to-male transmission.
• When an affected male fathers a pregnancy, all his daughters will be carriers and none of his sons will be affected.
• When a carrier female has a pregnancy, there are four possible outcomes, all of which are equally likely: normal daughter, carrier daughter, normal son, affected son—i.e. 50% of sons will be affected and 50% of daughters will be carriers.
The Y chromosome contains ~120 genes which mainly code for processes necessary to turn the fetus into a male.
The X chromosome contains >1000 genes (~1/20th of the genome), many of which are essential for normal growth and development.
Normal males have one X chromosome and normal females have two. In order that males and females have the same dose of the genes on the X chromosome, only one copy of the X chromosome is active in each a female cell, the other being mostly inactivated. X inactivation occurs in every cell in the female embryo 1–2 weeks after conception. X inactivation is a random process in the embryo, so there should be about 50% of cells containing the maternal X inactive and 50% containing the paternal X inactive.
Females with more severe symptoms due to a X-linked disorder may show unfavourably skewed X inactivation.
• Maternal inheritance: there are very few mitochondria in the sperm and many in the egg (paternal mitochondria constitute only 0.1% of the total in the fertilized egg), so the risk of paternal inheritance is essentially zero.
• Heteroplasmy: there may be two populations of mitochondria with different genotypes, and the level of mutant mitochondrial DNA has some effect on phenotype.
• Some conditions tend to cluster in families more often than would be expected by chance but do not follow a Mendelian pattern.
• These probably depend on a mixture of major and minor genetic factors and environmental factors.
• E.g. cleft lip/palate, neural tube defects, schizophrenia, IBD.
Looks at chromosomes under light microscopy, good for detecting mosaicism and for balanced translocations.
Detailed chromosome test (using DNA technology) for sub-microscopic deletions or duplications.
Targeted testing of gene suspected to cause the phenotype, good if only one or two genes which cause the condition, e.g. fibrillin 1 in Marfan syndrome.
Testing of a specified list of genes that can cause a phenotype/condition, good if many genes can cause a similar phenotype, e.g. Charcot–Marie–Tooth disease. When a panel of genes is tested, there is a higher chance of finding variants of unknown significance.
Tests all the protein-coding genes, mainly available through research studies although starting to be used in clinical practice. This is a good approach if conventional testing has not provided an answer, but the results may be difficult to interpret, including many variants of unknown significance.
Tests nearly the whole genome, including non-coding regions. More expensive than exome sequencing and will find many more variants, but may reveal mutations in regulatory sequences which can cause disease. Currently available through research studies, e.g. 100,000 Genomes Project, although it will come into clinical practice.
Honours
A variant is a change from the reference human genome sequence. A pathogenic variant or mutation describes a change that is disease causing. A ‘variant of unknown clinical significance’ means we are not sure if it is disease causing. A benign variant is a normal (often common) finding in the population, so should not be reported.
These relatively new tests are done using a sample of maternal blood to assess the genetic status of the fetus. Cell-free fetal DNA is extracted for testing. Fetal sexing looks for sequences from the Y chromosome to find out if the fetus is male or female. This is useful in X-linked recessive disorders, so that invasive testing can be offered if the fetus is male. It can also be used for sexing in disorders of sex development where ambiguous genitalia are detected on a prenatal ultrasound scan. Non-invasive prenatal testing refers to testing for common trisomies (Down syndrome, Edwards syndrome, and Patau syndrome). It can be viewed as a more accurate screening test, but is not as accurate as invasive testing. Non-invasive prenatal diagnosis can be offered for specific single gene disorders such as CF, spinal muscular atrophy, and achondroplasia. These tests mean that couples may be able to avoid an invasive procedure which causes an risk of miscarriage (chorionic villus sampling or amniocentesis).
It would be unusual to find a specific genetics station in your exams. As genetics covers all ages and systems, there are no specific genetics examination routines that you would be expected to perform. However, the skills you learn in genetics may help you in other stations, as follows.
• Taking a family history with relevant questions for the condition, e.g. heights, heart disease, sudden cardiac death, eye problems such as lens dislocation, myopia, and retinal detachment for Marfan syndrome.
• Drawing an accurate pedigree. (See Fig 16.1.)
Informed consent for genetic testing including benefits and harms from testing. Might include the possibility of finding a variant of unknown clinical significance, finding unexpected information, insurance implications, and implications for wider family.
Be careful with sharing information with other family members (ensure that the original patient gave permission to share information with the family).
Results of predictive test that shows that someone has inherited a mutation so is likely to develop a genetic disease.
E.g. about chromosomes and non-disjunction for Down syndrome, inheritance patterns.
Fig. 16.1 Example of a pedigree chart. Reproduced from Kasprzak et al. Invasive breast cancer following bilateral subcutaneous mastectomy in a BRCA2 mutation carrier: a case report and review of the literature. World J Surg Oncol. 2005; 3: 52, under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).