Symbols and conventions
≈ 25 minWorkbench: Pedigree
Pedigrees use an agreed set of symbols, so that a pedigree drawn in one clinic can be read in another. They were standardised by the US National Society of Genetic Counselors in 1995 and updated in 2008 and 2022.
Starting points
- Start with the person in front of you (the proband) and build up and out from them.
- Men are squares and women are circles. Since the 2022 update the symbol shows the person's gender identity. A transgender man is a square and a transgender woman is a circle, with their sex assigned at birth written underneath (AFAB, AMAB, or UAAB if unassigned at birth) when it is relevant. A diamond is used for a non-binary person, or when sex is not known.
- In a couple, the man is traditionally drawn on the left and the woman on the right. The 2022 update no longer requires this, because the symbols now show gender identity, so either order is acceptable: choose whichever keeps the pedigree clear.
- Brothers and sisters go from oldest on the left to youngest on the right.
- Affected people are shaded. If more than one condition runs in the family, use different colours or shade quarters of the symbol, and add a key.
The symbols
The whole table is also in the chapter.
Draw them yourself
Use your practice pedigree from the warm-up, or add new people to it. Every step ticks itself when the Studio can see the symbol. The show me buttons point at the control you need.
Activity 2.1 · People
- Select one person and switch on Proband (arrow) in the panel.
- Shade someone as affected: under Shading, choose Full and a colour.
- Mark one of the grandparents as Deceased.
- Under someone affected, write notes such as
Ann, 52 on one line and Breast cancer dx 45 on the next. “dx 45” means diagnosed at 45.
- Show “three brothers, all well” with one symbol: add a square, type
3 in the box under Inside the symbol and click Number.
- Mark someone as a carrier (a dot inside).
Activity 2.2 · Pregnancies and children
- Add a current pregnancy: select a parent, add a child, change the child's symbol to the diamond and put P inside.
- Add a pregnancy loss to a couple. Click Loss on the toolbar, then use Child under Connect: click the couple's relationship line, then the triangle.
- Make two brothers or sisters into identical twins: choose Twins under Connect, check that Identical is selected, and click the two children.
- Show that a child was adopted: select them and change their symbol to one of the bracketed ones.
- They were adopted into this family, so click the line above them and choose Dashed (adopted in).
Activity 2.3 · Relationships and the finishing touches
- Click a relationship line and choose Separated.
- Click Key on the toolbar and type what each colour means into the key.
- A pedigree is dated and signed. Choose More → Text label, click on the drawing and type today's date and your name.
Extension Draw two first cousins who have a child together. Add a grandchild to each of two brothers or sisters, then use Partners to join the two grandchildren. Pedigree Studio sees that they share grandparents and draws the double line by itself.
- Draw a consanguineous couple.
What to write under each symbol
Next to or under each symbol, write what you know about that person: their name, their age or date of birth, the age they died and the cause, and any medical conditions with the age at diagnosis. A healthy relative can be written as A&W (alive and well). Also remember to:
- Ask about consanguinity: “Are you and your partner related in any way?” and, if so, how.
- Record at least basic information on both sides of the family, even if the condition seems to be on one side only.
- Code the conditions if there is more than one in the family, and explain the code in a key on the chart so that others can understand it.
- Date and sign the pedigree, and note who gave the information.
Electronic pedigree programs such as PhenoTips and Progeny, and the Pedigree Studio you are using, help with all of these.
Reading a pedigree: the Okafor family
Now read a pedigree that someone else has drawn. The Studio numbers everyone by generation (Roman numerals) and position from the left, so that people can be referred to as, for example, III-2.
Activity 2.4 · Read the Okafor family
- Open the pedigree and look at it carefully before you answer the questions below.
What is the name of the proband?
Chidi, aged 7: the arrow is at the lower left of his symbol.
How many pregnancies has Amaka had, including the current one?
Four: Ada; the miscarriage in 2016; the twins Chidi and Dubem, who were one pregnancy; and the current pregnancy of 16 weeks.
Obi and Amaka are joined by a double line. How are they related to each other?
They are first cousins. Obi's father Emeka and Amaka's mother Grace are brother and sister, children of Nnamdi and Adanna. The double line shows that the partners are related by blood (consanguinity).
Click everyone in the Okafor family who has died.
Five people have a diagonal line through their symbol: Nnamdi and Adanna, Emeka, Samuel and Chioma.
Which features of this pedigree suggest that Chidi's hearing loss could be inherited, and how?
Chidi's parents are not affected but they are first cousins, and the condition has appeared in a child of theirs. Related parents are more likely to carry the same recessive variant, inherited from a shared ancestor, so this points towards autosomal recessive inheritance. Most inherited hearing loss that is present from birth is recessive, and many different genes can be involved. Note that Dubem being affected adds little: identical twins share the same genome, so they count once, not twice. Chapter 4 looks at patterns like this.
Why do you think the convention is to draw brothers and sisters from oldest on the left to youngest on the right?
It makes the pedigree quicker to read and compare, and it carries information without extra writing: you can see at a glance who is older. Birth order can matter clinically, for example when a condition starts at a certain age, when deciding who can be tested, or for conditions linked to maternal age. If following the convention would make lines cross, it can be relaxed, and ages written under the symbols.
Taking a family history and drawing it
≈ 45 minWorkbench: Pedigree
In this chapter you take the family histories of two patients. The patients are simulated: you choose what to ask, they answer, and you draw their family in the Studio as the answers come in. Then the page checks your drawing against the family.
What to collect
- Ask early on: “Has anyone in your family been seen by a genetics service, or had genetic testing?”
- For each person: their full name, date of birth or age, date of death or age at death, and medical information, with the age at diagnosis.
- What you need depends on why you are asking. In a family with cancer, for example, record the primary site of each cancer and the age at diagnosis.
- Ask about ancestry: “Originally, where did each of your grandparents come from?” Some variants are much more common in particular populations.
The information can be recorded as longhand notes, on a family history form, or straight onto a family tree, by hand or with pedigree software. In this practical you draw as you go.
How to ask
Top tips
- Make eye contact regularly, and use sensitive, respectful language.
- Ask clear, short questions: “Do you have any brothers and sisters?” “Do you all have the same parents?” “Is your mother still living?” “Has anyone in the family lost a baby?” “How old was your sister when she died?”
- Metaphors and quick comments are not always your friend: “when did they pass?”, or “great, thank you” straight after hearing about a death.
- Notice body language and what the person says, or avoids saying, about difficult subjects. Use tentative immediacy – sharing your sense of what the person may be feeling – to acknowledge painful areas.
- Give the person a contact number, so that they can add or correct details later.
Taking a family history can be quick and simple, or it can be a challenging and emotional experience – for the patient, for you, or for both. It can bring up deaths, divorce, loss of contact, non-paternity, adoption, gaps in what people know, family feuds, disabled brothers or sisters, the effects of disease, miscarriages, terminations and consanguinity. People with a genetic condition in the family may feel guilt (at passing a condition on, or at being unaffected), anger (at a parent, or an unaffected brother or sister), stigma, grief (for the life they cannot have, for their health, for relatives who have died) and anxiety about the future and the decisions they face.
It is not always straightforward. The person may start to cry, tell a long story, or struggle to remember dates of birth or causes of death. Handling these moments well is part of advanced genetic counselling practice, and it comes with experience. For now, notice them, stay kind, and record what is uncertain as uncertain.
Interview 1: Abena Mensah
The referral
Abena Mensah is 34. Her GP has referred her to the clinical genetics service because her younger brother died suddenly last year. Take her family history: choose questions from the topics below the conversation and draw her family in the Studio as you go. Ask in whatever order you like – but think about the order you would use in a real clinic.
Activity 3.1 · Draw the Mensah family
- Open your drawing for this interview (Interview 1: the Mensah family in the list above the Studio). It starts empty.
- Ask Abena why she has come, then draw her and mark her as the proband.
- Ask about her partner and children, and draw them all – including any pregnancies. Put each person's name and age under their symbol.
- Ask about her brothers and sisters, and draw them.
- Ask about her parents and their health, and draw them.
- Ask about both sides of the family, and draw both sets of grandparents and her parents' brothers and sisters.
- Ask all the important questions (the counter under the conversation shows how many you have asked).
- Add a key for the condition: click Key on the toolbar and type what the shading means.
- Add a text label (More → Text label) with the date and your name, as you would sign a pedigree in clinic.
Check your pedigree of the Mensah family. Fix anything that comes up and check again.
Which features of Abena's family history are warning signs of an inherited heart condition?
Kofi's sudden death at 28 during exercise, with hypertrophic cardiomyopathy at post-mortem and a variant in MYBPC3; her father now has the same condition; her grandfather Yaw died suddenly at 45; and her aunt Adwoa has a pacemaker for a reason the family does not know. Sudden cardiac death in a young person who seemed healthy is a warning sign on its own (see chapter 1).
Which pattern of inheritance does this family suggest?
Autosomal dominant: affected people in more than one generation (Kofi and his father, and probably his grandfather), with transmission from father to son, which rules out X-linked inheritance. Hypertrophic cardiomyopathy is usually autosomal dominant, and MYBPC3 is the gene most often involved.
Kofi's MYBPC3 variant is known. In what order would you offer testing for it to Abena's relatives, and why?
Start with Kofi's first-degree relatives. Testing his father Kwame first (affected, so very likely to carry it) would confirm which side of the family it comes from. Abena and Kwesi each have a 1 in 2 chance of carrying it. If Abena carries it, each of her children (and the pregnancy) has a 1 in 2 chance. Children in families with HCM are usually offered heart checks, and often genetic testing, because the condition can cause problems in childhood and adolescence – unlike the adult-onset conditions in chapter 5. If Kwame carries it, his brother and sister (Kojo and Adwoa) can be offered testing next, and so on down their branches. This step-by-step testing of relatives is called cascade testing.
Interview 2: Megan Price
The referral
Megan Price is 31. She has asked her GP about her family history of cancer. This time there are fewer prompts: take the history, draw the family, and check your pedigree at the end.
Activity 3.2 · Draw the Price family
- Open Interview 2: the Price family in the list above the Studio.
- Take Megan's family history.
- Draw her family. There is more than one condition, so use a different colour for each and add a key.
Check your pedigree of the Price family.
Why does it matter for the risk assessment that Amy was adopted?
Amy is not biologically related to the Price family, so she cannot have inherited a variant from Bill and Jean's side, and she should not be counted when looking for a pattern. Her own genetic risks come from her birth family, about whom little may be known. The brackets and the dashed line make this clear to anyone reading the pedigree.
Megan's mother was told in 2010 that no variant was found. Does that mean the cancers in this family are not inherited? What would you suggest?
Not necessarily. Genetic testing in 2010 looked at fewer genes, and was less sensitive, than testing now, and Megan does not know what was tested. The family history is striking: breast cancer at 42 in Karen, ovarian cancer at 50 in her sister Julie, and their mother Jean died at 47, possibly of breast cancer. It would be worth finding out what Karen's test covered and offering her up-to-date testing (in England, under the test directory's inherited breast and ovarian cancer indication). Testing an affected relative first is the most informative way to begin.
Which questions were hardest to ask, or to answer, and how would you handle them in a real clinic?
There is no single answer. Many people find questions about deaths, miscarriages, adoption and estrangement hardest. Acknowledging the person's feelings, asking short clear questions, explaining why you need the information, and recording uncertainty (“?breast cancer”) rather than pressing for detail the person does not have all help.
Patterns of inheritance
≈ 45 minWorkbench: Pedigree and Inheritance
The features of a family history give clues to how a condition is inherited, and the pattern of inheritance determines the risk to relatives. This chapter covers three patterns: autosomal recessive, autosomal dominant and X-linked.
Autosomal recessive
A person is affected only if they inherit two faulty copies of the gene, one from each parent. People with one faulty copy are carriers: they are not affected, but can pass the faulty copy on.
Activity 4.1 · Two carriers
- Open the Inheritance tab, choose Autosomal recessive and make both parents Carriers.
- Now tick We already know this child is unaffected.
Two carriers have a child. What is the chance that the child is affected?
1 in 4 (25%) for each pregnancy. The chance that the child is a carrier is 1 in 2, and the chance of being neither is 1 in 4.
Amelia has cystic fibrosis. Her brother David is not affected. What is the chance that David is a carrier?
2 in 3, not 1 in 2. Of the four equally likely outcomes, the affected one is ruled out because David is unaffected. Two of the three that remain are carriers. This assumes that the condition is fully penetrant and David would have shown symptoms if he were affected.
Features of autosomal recessive inheritance:
- Males and females are equally likely to be affected.
- Affected people are usually brothers and sisters, not parents or children of affected people – a “horizontal” pattern.
- Unaffected parents can have an affected child.
- The parents may be related. The rarer the condition in the population, the more likely it is that the parents of an affected child are related by blood.
- In small families the condition often appears in only one child.
Examples are cystic fibrosis and sickle cell disease. Cystic fibrosis affects about 1 in 2,500 babies born in the UK – around 240 a year. The glands' secretions are thicker than usual, which can block the small bowel in newborns (meconium ileus), causes thick mucus in the lungs with repeated chest infections and progressive lung damage, and causes pancreatic insufficiency with poor absorption of food and poor growth. Nearly all men with CF are infertile, because the vas deferens is absent or has not developed properly. It is the most common life-limiting recessive disease in people of Northern European descent, in whom about 1 in 25 people is a carrier; it is less common in other groups.
A cystic fibrosis scenario
Activity 4.2 · David and Lisa
- David's sister Amelia has CF. David and his partner Lisa are expecting a baby, and Lisa's family are of Northern European descent and have no history of CF. Open their pedigree.
- On the Inheritance tab, use the calculator at the bottom to work out the chance that the baby has CF.
Click everyone in this pedigree who must be a carrier (an obligate carrier).
Philip and Ruth, Amelia's parents. Amelia inherited one faulty copy from each of them, and neither is affected.
What is the chance that David and Lisa's baby has cystic fibrosis?
2/3 (David a carrier) × 1/25 (Lisa a carrier, from the population figure) × 1/4 (two carriers have an affected child) = 2/300 = 1 in 150.
Then the family remember that Lisa's grandfather John and David's grandfather Arthur were brothers – so Lisa and David are second cousins – and Lisa's father Michael has a carrier test.
Activity 4.3 · The effect of consanguinity
- Open the updated pedigree. Notice the double line between Lisa and David, and the dot showing that Michael is a carrier.
- Recalculate the chance that the baby has CF.
Michael is a carrier. What is Lisa's chance of being a carrier now?
1 in 2: she has a 1 in 2 chance of having inherited her father's faulty copy. (Her mother Anne could also be a carrier by chance, but that adds very little.)
What is the chance that the baby has CF now?
1/2 × 2/3 × 1/4 = 1 in 12, more than ten times higher than before. Most of that rise comes from Michael's carrier test, which takes Lisa's chance of being a carrier from 1 in 25 to 1 in 2. The shared ancestry is why the test was worth doing: Philip's variant may have come down from the great-grandparents, so John, and then Michael, could carry the same one. Without the test, the shared ancestry alone would raise the baby's chance only to about 1 in 60. Related partners are more likely to carry the same recessive variant, inherited from an ancestor they share.
Autosomal dominant
Inheriting one faulty copy is enough to be affected, or at risk. Each child of a person with the variant has a 1 in 2 chance of inheriting it, whether they are a son or a daughter.
- An affected person usually has an affected parent.
- Affected people appear in more than one generation – a “vertical” pattern.
- Males and females are equally likely to inherit the variant and be affected.
- Every kind of transmission is seen: father to son, father to daughter, mother to son, mother to daughter. Father-to-son transmission rules out X-linked inheritance.
Examples include inherited breast cancer and Huntington's disease. Two things make dominant pedigrees harder to read:
Penetrance
The proportion of people with the variant who develop the condition. Inherited breast cancer shows reduced penetrance: a BRCA variant raises the risk, but not everyone with it develops cancer. Huntington's disease shows complete penetrance: people with the full expansion develop it if they live to the age of onset.
Variable expressivity
The same condition can show itself differently in different people. Neurofibromatosis type 1 can be mild or severe, even within one family. In Huntington's disease the age of onset and severity can vary between generations, largely because of anticipation: the CAG repeat can lengthen as it is passed on, especially from a father, and longer repeats tend to start earlier.
A BRCA2 scenario
Activity 4.4 · Jane and Adam
- Jane is pregnant. Her partner Adam's elder sister had breast cancer at 34 and was offered genetic testing (in England, test directory indication R208 includes breast cancer under 40). A pathogenic variant in BRCA2, c.5946delT, was found. Open the pedigree.
What is Adam's chance of carrying the BRCA2 variant?
1 in 2. His sister inherited it from one of their parents. Their mother had breast cancer at 47 and her sister had ovarian cancer, so it almost certainly came from their mother, and each of her children had a 1 in 2 chance of inheriting it.
What is the chance that Jane and Adam's baby has inherited the variant?
1/2 × 1/2 = 1 in 4. If Adam is tested, this becomes either 1 in 2 or close to zero.
Why was it useful to know that the family has Jewish ancestry?
Three BRCA1 and BRCA2 variants are much more common in people with Ashkenazi Jewish ancestry because of a founder effect, and BRCA2 c.5946delT is one of them. Ancestry makes a BRCA variant more likely, can lower the threshold for testing, and allows a quick test for the common variants.
Adam is a man. Why might testing still matter to him and his family?
Men with BRCA2 variants have a higher risk of prostate cancer (often more aggressive), male breast cancer and pancreatic cancer than other men, so they may be offered screening. And if he carries it, each of his children, sons or daughters, has a 1 in 2 chance of inheriting it. The variant can pass through unaffected men, which is one reason inherited breast cancer can seem to “skip” a generation.
X-linked
The gene is on the X chromosome. Males have one X chromosome, so one faulty copy affects them. Females have two, so with one faulty copy they are usually carriers.
Activity 4.5 · Fathers and mothers
- On the Inheritance tab, choose X-linked recessive with an affected father and a mother who is not a carrier.
- Now an unaffected father and a carrier mother.
Father affected
All his daughters inherit his X chromosome, so all are carriers (some have mild features). None of his sons are affected: sons get their father's Y chromosome, not his X. So there is no male-to-male transmission.
Mother a carrier
Each son has a 1 in 2 chance of being affected, and each daughter a 1 in 2 chance of being a carrier.
In both cases more males are affected than females.
Which pattern?
Open each family in turn and decide which pattern of inheritance fits it best. The questions explain each answer.
Activity 4.6 · Four families
Family C: click everyone who must be a carrier (the obligate carriers).
Four women: I-2 (her son II-4 is affected and her husband is not), II-2 (mother of the affected III-1), III-2 (mother of the affected IV-1) and III-4 (daughter of the affected II-4: every daughter of an affected man inherits his X chromosome).
Family D: click the person who must carry the variant even though they are not affected.
II-3. His mother I-2 and his daughter III-3 are affected, and the variant can only have reached III-3 through him (her mother II-4 married into the family).
Family histories in gene discovery and variant interpretation
Careful study of a condition across many families can lead to new genes. Some families meet the diagnostic criteria for neurofibromatosis type 1 – an autosomal dominant condition, caused by variants in NF1 on chromosome 17, that usually presents with several café-au-lait patches – but have no NF1 variant. In several such families, everyone affected had café-au-lait patches and freckling in the armpits but no neurofibromas, and all were found to have a variant in a different gene, SPRED1, that segregated with the condition (J Med Genet 2009;46:425–430). The gene was first linked to this condition by Brems and colleagues in 2007, and it is now called Legius syndrome.
A variant of uncertain significance (VUS) is found in a woman with a rare condition. How could her family help decide whether it causes the condition?
By segregation analysis: test her affected and unaffected relatives. If the variant is found in every affected relative, and not in unaffected adults who are past the usual age of onset, that supports it causing the condition; each additional informative relative adds evidence. If an affected relative does not have it, it is unlikely to be the cause. The pedigree shows who is worth testing and how informative each result would be.
Ethical dilemmas: families, not just individuals
≈ 45 minWorkbench: Pedigree
A genetic result about one person is also information about their relatives. That simple fact is behind most of the ethical problems in clinical genetics. This chapter works through five families, using their pedigrees.
Thinking about ethics in genetics
There is often no single right answer, and several ethical issues can arise in the same family. Professional guidelines help, by giving precedent and consistency, as does discussion in a multidisciplinary team. Communication and documentation matter. Useful principles to think with are confidentiality, beneficence (doing good), non-maleficence (avoiding harm), justice (fairness) and autonomy. For each scenario, ask: what are the possible harms and benefits, who do they apply to, and what might help?
Each scenario is a different family, except that scenario 5 returns to the family in scenario 3. Some first names (Brian, Bob, Gwen, Philip and Helen) appear in more than one family, so check which family you are looking at. In these pedigrees a dot marks someone who has the family's variant but no symptoms yet; strictly, the NSGC symbol for this is a vertical line (see the ).
Scenario 1: Lynch syndrome
The family
Alice, 50, had bowel cancer at 45. An MLH1 variant that causes Lynch syndrome has been found in her, her late sister Gwen and her uncle. Brian, Gwen's widower, does not want his children to know about the family's variant, and Alice is concerned. Her sister Ann and her cousin Bob have declined genetic testing, but want to carry on having colonoscopies every two years. They have not discussed it with their children.
Activity 5.1 · Who is at risk?
- Open the Lynch syndrome pedigree and find Alice, Brian, Ann and Bob.
Click everyone who has a 1 in 2 chance of carrying the MLH1 variant.
Five people: Ann (Alice's sister – their father must have carried it), Gwen's two daughters, and Gary and Bob, the sons of Alice's uncle, who has the variant.
Click everyone who has a 1 in 4 chance of carrying it.
Ann's two daughters and Bob's two children. Their parents have a 1 in 2 chance and have not been tested. If Ann's daughters were tested and one carried the variant, that would reveal that Ann carries it too.
Brian does not want his daughters, now 26 and 24, to be told. What are the competing interests, and what would you do?
Gwen's daughters are adults with their own autonomy, and each has a 1 in 2 chance of a variant for which there is effective prevention: colonoscopy every two years from 25 for MLH1 carriers, which reduces deaths from bowel cancer, daily aspirin, and later on a discussion of their raised risk of womb and ovarian cancer (beneficence; harm from not knowing). Brian may want to protect them, may be grieving, or may feel guilty or anxious: all common reasons for not passing on genetic information (see the table below). The information is not only his: it comes from Gwen's and Alice's results, and Alice could tell her nieces herself. A sensible approach is to explore Brian's reasons, explain what the daughters could gain, and support Alice in sharing the information, for example with a family letter, offering to review it later. Professional guidance accepts that in exceptional cases a clinician's duty may extend beyond their own patient – but information should only be passed on if it brings a direct benefit, after weighing the interests involved, and the reasoning should be documented.
Ann and Bob have declined testing but want colonoscopies every two years. Is that reasonable? What about their children?
It is their right not to know their genetic status, and colonoscopy as if they carried the variant protects them against bowel cancer. It does not cover everything, though. If Ann carries the variant, she also has a high chance of womb (endometrial) cancer and a raised chance of ovarian cancer, which colonoscopy does not detect. Carriers are also offered daily aspirin, and women can consider risk-reducing gynaecological surgery once they have completed their family. Without a test, Ann cannot weigh up those choices on good evidence. There are other costs too: half of people in their position do not carry the variant and would be having colonoscopies (which have their own small risks) for nothing, which raises a question of justice in the use of NHS resources. Their children are adults at 1 in 4 risk who have not been told; testing them could reveal their parents' status. Encourage Ann and Bob to talk to their children, and offer help with that.
| Reasons people give for not telling relatives | What can help |
|---|
| They have no contact with the relatives, but want them to know | Trace the relatives through the NHS and send the information to their GP |
| Communication in the family is poor or complicated | Discuss how the information could be passed on, and help if asked |
| They have not yet come to terms with the diagnosis; they fear guilt or blame; they want to “protect” their relatives | Talk openly about these concerns, and agree to come back to the question later |
A case that reached the courts
In ABC v St George's Healthcare NHS Trust (High Court, 2020), a woman whose father had Huntington's disease was not told about it while she was pregnant, because he had asked his doctors not to tell her. The court held that the clinicians closely involved with her owed her a duty to balance her interest in knowing her genetic risk against her father's interest in confidentiality. Her claim failed: not telling her was a decision a responsible body of doctors could reach, and she had not shown that she would have ended the pregnancy.
| Predictive (presymptomatic) testing: possible benefits | Possible drawbacks |
|---|
| Certainty about the future; being able to plan life and career; a sense of control; reproductive choices; treatment or prevention for some conditions; information for relatives | Uncertainty can be more comfortable; bad news can be hard to adjust to; the burden of telling relatives; implications for career, lifestyle and insurance; effects on family relationships |
Informed decision-making and non-directive counselling are essential.
Scenario 2: Huntington's disease
The family
Brian, 65, has Huntington's disease, as did his father Bob. His children, Anne (46) and Philip (39), can have predictive testing. Anne does not want to know her status, but her daughter Claire (24) does.
Activity 5.2 · Testing by proxy
- Open the Huntington's disease pedigree.
What is Claire's chance of having inherited the HD expansion?
1 in 4: Anne has a 1 in 2 chance of having inherited it from Brian, and if she has, a 1 in 2 chance of having passed it to Claire.
If Claire is tested and has the expansion, whose genetic status would that reveal? Click them.
Anne's. Claire can only have inherited it through her mother, so a positive result for Claire shows that Anne has it too – the very thing Anne has chosen not to know. This is called indirect testing, or testing by proxy.
How would you approach Claire's request?
Claire has a right to be tested, and Anne has a right not to know; both cannot be fully respected if Claire tests positive. Weigh up both rights; counsel Claire about what a result would mean for her mother (and her sister and daughters); encourage the family to talk to each other; and offer support to everyone affected. Claire might choose to talk to her mother first, or to delay testing, but in the end the decision is hers.
Scenario 3: testing children
The family
May, 49, has early-onset familial Alzheimer's disease (EOFAD), as did her father Henry. Her daughter Sally (29) has had a predictive test and has the family's EOFAD variant, though she has no symptoms. Sally wants to know whether her son Ryan, who is 6, has inherited it. May's husband Tom has von Hippel–Lindau disease (VHL), and so does their daughter Emma (24), who is worried that her son Sean, also 6, has VHL.
Activity 5.3 · Two six-year-olds
- Open the pedigree. Find Ryan and Sean.
Click the child for whom a genetic test now could change their medical care.
Sean. VHL causes tumours that can start in childhood, and children at risk are offered regular surveillance from a young age. A negative test would spare him years of check-ups; a positive one would make sure he has them.
Why would Ryan usually not be tested now, even though his mother wants him to be?
EOFAD starts in adulthood and nothing can be done in childhood to prevent it, so testing Ryan now would bring no medical benefit and would take away his own choice about whether to know. Guidance is that children are usually tested only when the result would affect their care in childhood; for adult-onset conditions, testing waits until the young person can decide for themselves, usually from 18, although exceptions are sometimes made. The welfare of the child is what matters most, it helps to involve the child as far as possible, and this can be hard for parents to accept.
Scenario 4: reproductive decisions
The family
Martha (23) has the Huntington's disease expansion, like her mother Helen. She and Garth are 8 weeks pregnant and do not want a baby with the expansion. At 12 weeks they have chorionic villus sampling (CVS), which shows that the baby has it, and Martha decides that she does not want to end the pregnancy. Her sister Josie (25), who has separated from her partner, is also 8 weeks pregnant. Josie does not want to know whether she will develop HD herself.
Activity 5.4 · Two pregnancies
- Open the pedigree.
A couple at risk of having a child with a serious inherited condition can choose to have a child in the same way as anyone else, or to use prenatal diagnosis, pre-implantation genetic diagnosis (testing embryos made by IVF), donated eggs or sperm, or adoption. Prenatal diagnosis is available when the genetic cause is known and the condition is serious. It is often done by chorionic villus sampling (CVS): a small sample of the placenta, taken from about 11 to 14 weeks of pregnancy. A result for a single gene is usually ready within about a week, and a full chromosome analysis in about two weeks. CVS carries a small chance of miscarriage. Older sources give 1–2%; the NHS now quotes less than 1 in 200 for most pregnancies.
These are difficult decisions about wanted pregnancies. Couples weigh up the effect on the family of an affected child and that child's quality of life, and their religious, cultural and family beliefs matter.
Martha decides to continue the pregnancy after the test shows the baby has the HD expansion. What ethical issues does this raise for the future child?
It is equivalent to a predictive test on a child for an adult-onset condition: the child will grow up with their HD status already known, without having chosen to know it. How will this affect their upbringing? When and how will they be told? How will they feel about their parents' decision? These implications are discussed in depth with couples before prenatal diagnosis, and there is usually an expectation that an affected pregnancy will be ended – but couples may still decide to continue, and all the team can do is make sure they understand the ethical complications.
Josie has exclusion testing, which shows whether the baby inherited the chromosome 4 that Josie received from her affected mother Helen (“high risk”) or from her father (“low risk”). The result is high risk. What is the baby's chance of having the HD expansion?
1 in 2 – the same as Josie's own chance. The baby has Helen's chromosome 4; whether that copy carries the expansion is exactly what Josie has chosen not to find out. Josie decides not to end the pregnancy, so her child will grow up at 1 in 2 risk – and if the child is ever tested and has the expansion, that would reveal Josie's status too.
Scenario 5: what a genome can reveal
The family
Back to May's family from scenario 3 (a different Helen from scenario 4). Helen, 22, is May's youngest daughter. Her baby Sienna, 18 months old, has profound hearing loss from birth and has her genome sequenced to look for the cause. The genome also shows that Sienna has the family's variant for early-onset Alzheimer's disease.
Activity 5.5 · An unexpected finding
- Open the pedigree.
This pedigree is drawn as the hearing team would see it, without the family's Alzheimer's disease. You know from scenario 3 that May has EOFAD. Whose genetic status does Sienna's result reveal, although they never asked to know it? Click them.
Helen, Sienna's mother: Sienna can only have inherited the family's variant through her. Helen is 22 and had not asked to know.
The test was done to find the cause of Sienna's hearing loss. Should the EOFAD finding be reported? Think about Sienna, Helen and the rest of the family.
Points to consider: the finding gives Sienna, a child, a predictive result for an adult-onset condition with no benefit in childhood, taking away her future choice; it reveals Helen's status without her having chosen to know; and it changes the picture for Helen's relatives. On the other hand, the information exists, and might matter to Helen's own decisions, for example about future pregnancies. Genomic tests can generate unexpected or incidental findings that are hard to explain, and whether findings that cannot be acted on should be fed back is a question that consent for genomic testing has to address in advance. Clinical genome tests in the NHS are designed to answer the clinical question, which limits findings like this one.
Consent, confidentiality and genetic data
For consent to be legally valid, the person must have enough appropriate information to make the decision, must be competent to make it, and must give it voluntarily. Case law suggests that “appropriate” information should be patient-centred: what a reasonable patient would want to know, as well as what this particular patient wants to know. Consent in genomics raises particular issues:
- Is the test clinical care or research? They are governed very differently.
- Genomic tests can generate additional, unexpected or incidental findings, which may be hard to explain.
- Variants can be of uncertain significance because there is not enough evidence to classify them.
- Should variants that cannot be acted on be fed back to patients?
- Genetic information about one person allows inferences about the people they are related to.
In the UK, personal data are governed by the Data Protection Act 2018 and the UK GDPR (both since amended by the Data (Use and Access) Act 2025). Genetic data are “special category” personal data, as are, among others, data concerning health and biometric data used to identify someone. Data that can identify a person indirectly – for example data with a study number instead of a name, which could be linked back to the person – can still be personal data. Truly anonymised data are not. The Information Commissioner's Office says that genetic data with enough markers to be unique to an individual is personal data even without a name, although some, such as the PHG Foundation, argue that genomic data are not identifiable unless they can be linked back to a person. Safeguards include managed access, de-identification, the Caldicott principles, trusted research environments and research ethics review.
Ways of reasoning about ethics
| Approach | In short | A common criticism |
|---|
| Consequentialist ethics | What is right is whatever makes the world better in the future; utilitarianism seeks the greatest benefit for the largest number | Can it justify sacrificing someone, or something, for a greater good? |
| Duty-based ethics | Actions are right or wrong in themselves; never treat people only as a means to an end; human rights | Which duties are absolute, and which can be negotiated? |
| Virtue ethics | Focus on moral character: what would a good person do? | Good intentions do not guarantee good outcomes |
| Ethics of care | Focus on relationships; from “what is right?” to “how should I respond?” | Actions and consequences matter too |
| Principlism | Autonomy, beneficence, non-maleficence and justice | Often puts autonomy above other concerns, and can be applied mechanically |
Eugenics never left?
Genetics began, in part, as a science of breeding. In the late 19th and early 20th centuries, scientific and political worries about “degeneration” led to eugenics: coercive eugenics used force to try to improve the population, while non-coercive eugenics used education, information and social norms. The distinction is not sharp, and it does not map neatly onto right and wrong. Medical genetics is sometimes accused of being a “new eugenics” working at the level of the gene. When prenatal screening is standard care, every pregnant woman has to consider the choice whether or not she sought it out; the number of babies born with Down syndrome in England and Wales is well below what it would be without prenatal diagnosis (Wu & Morris, Eur J Hum Genet 2013). Genome-wide association studies of traits such as educational attainment have also been reported in the press in ways their authors may not have intended.
Is the work you are part of safe from eugenic connections? Choose a piece of genetics or genomics work you know about. How could it be used, or reported, in ways its authors did not intend, and what could they do about it?
There is no single answer. Good answers recognise that researchers are responsible for the questions their research asks; that results about groups or traits can be misreported or misused; and that steps such as involving patients and the public, careful choice of research questions and population descriptors, clear communication of what results do and do not mean, and being willing to decline to take part all help.
Which of the five scenarios did you find hardest, and why?