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Genetics: Family history and risk assessment

That illness can ‘run in families’, because related family members will each share some of their genetic code and often live in or share similar environments, is a familiar concept. As a result, multiple individuals within a family may be diagnosed with the same or similar condition.

Key points

  • Family history is the key trigger point in identifying people who might benefit from referral to genetic services
  • Learn the ‘red flags’ to look out for within the patient group you are most in contact with.
  • Know what to do if you think someone’s family history might merit further investigation.

The inheritance pattern that a disease displays as it is passed between family members can enable health professionals to determine the likelihood of the condition occurring in another family member or subsequent pregnancy.

Regional genetics teams are happy to take (telephone) enquiries from health professionals. If you are concerned that a patient might benefit from additional information but are unsure about whether or how to refer - call them. Know how to contact your regional genetics team. (See resource list for details).

Family history provides a useful tool to identify individuals who may have, or be at risk of developing an illness with a genetic component. Asking a patient about their family history may also provide additional information that will enable a diagnosis to be made.

A typical question that you might hear:
My aunt has been diagnosed with ‘X’ [condition] - am I at risk?

Common conditions
Most illnesses are caused by a combination of genetic and environmental factors. Whilst we all carry the same genes, the genetic code of each can vary subtly. When particular combinations of these gene variants are present with additional input from environmental influences (e.g. diet or smoking) disease can result. Research is now beginning to identify the combinations of genes involved in common conditions like heart disease and asthma. The complex nature of these conditions means that whilst the condition may appear to ‘run in a family’ there is no predictable pattern of inheritance and it is currently not possible to predict who will/will not become ill. Environmental components often have a greater influence on the development if this type of disease. Nurses and midwives play a significant role in providing ‘public health’ advice to individuals who may be at increased risk by providing information on lifestyle management. Making lifestyle adjustments (e.g. smoking cessation or changes to diet) can help to counter the effects of their genetic makeup.

Single gene and chromosomal conditions
A condition resulting from a change in a chromosome or single gene can be passed on with a predictable pattern of inheritance to other family members. Specific family members may be at increased risk due to their relationship (e.g. parent, child, sibling) to an affected family member.

In order to answer a question like the one above it is important to establish the disease involved and the probable inheritance pattern that is usually associated with it. A detailed family history should be taken and the risk assessed formally. For some conditions such as breast and bowel cancer there may be local guidelines available which can help a health professional assess if the risk is increased enough to warrant a referral to a genetic centre (e.g. age at diagnosis of the family member(s) and how closely related they are to the person seeking advice). Whatever the condition, the risk will depend on the family history and the relationships between the affected people. If the patient is referred to genetics there is no need to discuss the risks in detail as the genetic centre can do this. This approach can be preferable as it reduces the chance of conflicting advice!

Sometimes the signs and symptoms of a genetic condition differ between family members and may appear to be unrelated or the pattern of inheritance confusing. It is important not to give false reassurance, but to find out further information, referring to the genetics service where appropriate. For the ‘worried well’ (ie those that have no symptoms but are concerned that they may develop a condition in the future) knowledge of the condition by the health professional is important. For example, one common misconception is that the familial (inherited) forms of breast cancer cannot be passed on by men. Conversely, patients should not be referred unnecessarily if they can be reassured that they are not at risk. Information is now easily accessible from credible sources via the internet (e.g. NHS Evidence - genetic conditions http://www.library.nhs.uk/geneticconditions/) and regional genetics teams are happy to take (telephone) enquiries from health professionals who wish to discuss a query before talking to a patient.

Considering a referral?
Discuss the case with the patient’s doctor, other colleagues and the genetics team as appropriate. Explain the procedure to the patient and what they can expect from a genetic appointment (see Genetic Testing: What it does and doesn’t do).

A typical question that you might hear:
There’s no history of X’ [condition] in the family, so why has this happened now?

Sometimes people make the assumption that because a condition is genetic there should always be a family history, i.e. other members of the family should have had the condition. Whilst this is often true, there are a number of reasons why this might not always be the case. They include:

- The condition may not have previously been recognised / diagnosed in other family members.

- The genetic alteration is newly arising in this family member

- The alteration has been passed through previous generations by unaffected ‘carrier’ family members

Unrecognised
Sometimes the clinical manifestation of the same gene change may be different in related individuals. For example women with Hereditary Non-polyposis Colon Cancer (HNPCC) may develop endometrial cancer and both males and females are also at risk of stomach cancer. Taking an accurate family history can be very helpful. Sometimes conditions are not diagnosed, but on further examination of the available information, other family members may also be found to have/had the condition. (Click here to see Helen’s story).

Also, it is not uncommon for information of an illness not to be discussed or shared within a family. (Click here to see Kiran’s story)

Newly arising (de novo)
Changes to our genetic code occur frequently (and are usually repaired) when the DNA is copied or chemically altered (e.g. as the result of sun damage). These newly arising changes are said to be de novo. Of the changes that are not repaired, some have no effect whilst others will alter an individual’s phenotype (physical characteristics) and may result in an illness. For example a localised acquired change leading to melanoma. If a change is present in the tissues that produce egg or sperm cells, the change can be passed onto offspring.

Unaffected carrier
The inheritance pattern of a genetic condition is dependent on the type and location of the gene change. Some conditions can be passed down through families by ‘carriers’ who are often unaffected and completely unaware until a child is born with the condition. Examples are given below

  • Recessive conditions require the presence of two altered copies of a gene. Children with a recessive condition (e.g. cystic fibrosis) are born to parents who will both carry a gene change.
  • Genes that are altered on the X chromosome are said to be X-linked and cause conditions that include Duchenne muscular dystrophy and haemophilia. Males are affected by X-linked conditions much more frequently. As they have only one copy of the X chromosome (plus a copy of the Y chromosome) the presence of an altered gene is sufficient to cause the associated condition. Females have two copies of the X chromosome; one altered copy is often insufficient to cause the condition although a proportion of females may have some (more mild) symptoms. Females can therefore ‘carry’ the gene change and pass it on without knowing until an affected son is born in the family.
  • Chromosomes, the structures in our cells on which genes are located, can sometimes break and rejoin in the wrong place (translocation). If there is no gain or loss of the genetic material then the translocation is said to be balanced and the individual is usually unaffected. However, during cell division to produce eggs and sperm the chromosomes are distributed amongst the gametes - one copy of each pair of chromosomes per cell. The translocated chromosomes can be passed on. If at conception the genetic material does not remain ‘balanced’ the pregnancy will be affected.

Practice Point
Being able to recognise when a condition could be inherited (particularly in the absence of family history information) can be crucial for appropriate diagnosis, treatment and management of your patient and other family members. Ask yourself, could there be a genetic component to this?

A typical question that you might hear:
My grandfather has some signs of X’ [condition], but my father didn’t. How has it skipped a generation?

This is an example of a question you may face as a practice nurse, in a specialist clinic, or at a booking appointment if you are a midwife. Patients who have received a diagnosis or who have been referred for further tests pending a diagnosis often ask how a condition ‘skips a generation’.

There are a number of possibilities

  • Your patient and his/her grandfather may have different conditions.
  • The condition might be so variable that your patient’s father is mildly affected and has gone undiagnosed.
  • It might be that his/her father has the same gene change as the grandfather but the condition has not clinically manifested yet. (see Penetrance below)

Variability
Most conditions are caused by a combination of genetic and environmental factors. Even with conditions that are referred to as ‘single gene’ or Mendelian (because of their predictable pattern of inheritance first identified by Gregor Mendel) the outcome of the gene change may be modified by the individual’s overall genetic makeup and the environment in which they live (see Fig. A). The result is that the type and severity of the clinical features of a condition can vary (sometimes significantly) between members of the same family.

Reproduced with permission from the American Society for Clinical Investigation, Manolio T et al., 2008, A HapMap harvest of insights into the genetics of common disease, J Clin Invest 118: 1590

Reproduced with permission from the American Society for Clinical Investigation, Manolio T et al., 2008, A HapMap harvest of insights into the genetics of common disease, J Clin Invest 118: 1590

A. Single gene disorders. A variant in a single gene is the primary determinant of a disease and is responsible for most of the disease risk or trait variation (dark blue sector), with possible minor contributions from modifier genes (yellow sectors) or environment (light blue sector).

B. Complex disease. Many variants of small effect (yellow sectors) contribute to disease risk, along with many environmental factors (blue sector).

Common conditions (e.g. diabetes and heart disease) can display even more variability because of the greater number of genes involved (Fig. B). The complex nature of these conditions means that whilst the condition may appear to ‘run in a family’ there is no predictable inheritance pattern and ‘skipping of a generation’ appears to be present. Environmental components often have a greater influence on the development if this type of disease. Nurses and midwives play a significant role in providing ‘public health’ advice to individuals who may be at increased risk. Making lifestyle adjustments (e.g. smoking cessation or changes to diet) can help to counter the effects of their genetic makeup.

Penetrance
Penetrance is the proportion of individuals with a gene change (mutation) causing a particular disorder who exhibit clinical symptoms of that disorder. A condition, (most commonly inherited in an autosomal dominant manner), is said to show complete penetrance if clinical symptoms are present in all of those who have the disease-causing change. To have reduced or incomplete penetrance means clinical symptoms are not always present in individuals who have a disease-causing change. An example of an autosomal dominant condition showing incomplete penetrance is familial breast cancer due to mutations in the BRCA1 gene. Females with a mutation in this gene have an 80% lifetime risk of developing breast cancer.

Understanding the likelihood of a condition occurring more than once in a family

The likelihood of a condition occurring more than once in a family will depend upon the condition.

Conditions that are caused by a change in a single gene can be passed on through successive generations of a family and can show a distinctive pattern of inheritance. The type of pattern provides a way to determine the likelihood that the condition could occur again (recurrence risk).

Genes are the instructions that tell the body how to grow and develop. We inherit one set of instructions (around 22,000 genes) from our father (through the sperm) and the other from our mother (through the egg). Genes are carried on structures called chromosomes. Changes in a gene can alter the way a gene works with some changes causing disease. In some conditions only one copy of a gene is altered (dominant). In other conditions both copies of the gene are altered (recessive).

A typical question that you might hear:
After my daughter was diagnosed with ‘X’ [e.g. cystic fibrosis, sickle cell disease] the doctor/midwife told me there was a 1 in 4 chance of this condition occurring. We are only going to have 2-3 children, so the other(s) should be OK, shouldn’t they?

Conditions with a recessive inheritance pattern e.g. cystic fibrosis and sickle cell disease require changes in both copies of the same gene to cause the disorder. When only one change is present the individual is said to be a carrier (and is usually unaffected by the condition). The condition arises when both parents are either carriers or are affected and each pass on an altered gene to a child.

In the diagram, both parents have one regular copy of a gene (blue) and one altered copy (orange). Both parents are carriers.
Every sperm or egg that they produce will contain either a regular or an altered copy.
For every conception there are 4 possible combinations of this gene pair that can occur:
- There is a 3 in 4 (75%) chance that the child would be unaffected
- There is a 2 in 4 (50%) chance that the child would be a carrier
- There is a 1 in 4 (25%) chance that the child would be affected

NB If a child is unaffected, there is a 2 in 3 chance that (s)he is a carrier

 

 

 

Practice Point
For this question the parent(s) need to be aware that there is a 1 in 4 (25%) chance that any subsequent children would also have the condition.
Ensure that (s)he is given the opportunity to discuss this further with a GP, midwife or member of a regional genetics team.

Other patterns of inheritance will give rise to different recurrence risk for subsequent pregnancies.

The diagram to the left illustrates dominant inheritance, where a change in only one copy of a gene is sufficient to cause a disorder. Familial Hypercholesterolaemia, Huntington disease and Marfan syndrome are examples of dominantly inherited conditions.
Here, one parent is affected - illustrated by the orange altered gene.
Every sperm or egg that he/she produces will contain either a regular or an altered copy. If their partner is unaffected there are 2 possible combinations of this gene pair for every conception:
- There is a 2 in 41 (50%) chance that the child would be affected
- There is a 2 in 41 (50%) chance that the child would be unaffected

1This is sometimes written as 1 in 2

Two of the chromosomes that carry the genetic material within our cells are referred to as the sex chromosomes. They provide the information which determines the sex of an individual. Females have two X chromosomes and males have one X and one Y. The Y chromosome does not carry the same genes as the X.

Conditions that result from changes in a gene on the X chromosome are referred to as X-linked. Most frequently seen are recessive in inheritance - see diagram below. Examples include haemophilia and Duchenne muscular dystrophy. X-linked dominant inheritance is rare.

Typically:

  • Males are affected much more frequently
  • Passed on through carrier females to their sons
  • Carrier females tend to be unaffected (because they have a regular copy of the gene present on the other X chromosome)
  • Affected males cannot transmit the disorder to their sons (This is because they can only pass on the Y chromosome to their sons. Men always receive the X chromosome from their mother.)

 

 

Mitochondrial inheritance
Sub-cellular structures known as mitochondria also contain a small amount of genetic material. Mitochondria are always passed on by the mother. Therefore conditions that result from changes to mitochondrial genes can demonstrate a maternal pattern of inheritance, i.e. always passed on by female members of the family, never by males. Both men and women can be affected.

Translocation
During cell division to create egg and sperm cells, chromosomes pair up and exchange genetic material. Normally the exchange takes place between the same two regions of DNA (one region on the maternal chromosome and the other on the paternal copy of the same pair). This exchange is one mechanism for creating diversity and variation between individuals.

Occasionally, chromosomes will break and re-join incorrectly creating a ‘translocation’. If there is no overall loss of material then the translocation is said to be ‘balanced’. A translocation may or may not cause disease.

One chromosome from each pair is then distributed into the gamete cells (eggs or sperm).

A potential problem can arise at conception if there is an imbalance in genetic material (see figure). Unbalanced translocations are often the reason for a family history of multiple miscarriage.

New mutation
Changes to our genetic code occur frequently and are usually repaired. Of the changes that are not repaired, some can alter an individual’s phenotype (physical characteristics) and may result in an illness. Only changes that present in the tissue that will form egg or sperm cells can be passed on. Changes that are localised to other cells and tissues of the body cannot be passed on.

Many children are born with conditions that result from a newly arising gene change. It is not always possible to predict exactly when this occurs. If the change is believed to have occurred very early on in fetal development, the likelihood that this could happen again by chance in a subsequent pregnancy is low. However, it is possible that one parent carries the gene change in tissue that goes onto form sperm or egg. As there is no way to test all the egg or sperm cells from the parents it is not possible to offer a test to give parents complete reassurance that it won’t happen again. Expert genetic counselling is necessary to ensure that parents fully understand the recurrence risk in these situations.

Alterations in chromosome number (aneuploidy)
Conditions due to a change in chromosome number can arise because of an error during cell division. Usually, chromosomes segregate so that there is one copy of each pair in the resulting cells. Failure to separate correctly can result in the gain or loss of material (e.g. Down syndrome (T21) - three copies of chromosome 21 and Turner syndrome (XO) - missing a sex chromosome). Some, but not all aneuplodies can be associated with an increased maternal age. When families are asking questions about recurrence risk in subsequent pregnancies, a referral to the genetic department for specialist counselling is recommended.

Common conditions.
There are many conditions that we recognise as being ‘passed on through families’ e.g. asthma, heart disease and diabetes. These conditions result from multiple gene variants (each with an individually small effect) and environmental factors (e.g. smoking, diet, exercise). Due to the complexity, these conditions do not have a predictable pattern of inheritance.

These questions were written by staff at the NHS Genetics Education and Development Centre

Resources

The NHS National Genetics Education and Development Centre provides support for health professionals to learn more about genetics and its relevance to professional practice. A series of fact sheets ‘Understanding Modes of Inheritance’ will be available shortly.

Taking and Drawing a Family History - a downloadable step-by-step guide

Contact details for all UK regional genetics centres are available from the British Society of Human Genetics and from the Genetic Interest Group (a national alliance of patient organisations)

NHS Evidence - a source of information on genetic conditions for staff working in non-genetic disciplines

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