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Genetics

Geneticist Dr Phil Zack answers questions from GP Dr Peter Stott on new and future developments in this field

Geneticist Dr Phil Zack answers questions from GP Dr Peter Stott on new and future developments in this field

1. What is actually done when we refer patients to a specialist in genetics? How important is the family history versus the lab test? Are some problems treated differently?

Clinical genetics is in many ways a medical specialty just like any other. And like any specialist referral, the answer depends on the referral question. Typical referral reasons might be:

  • a person with a genetic condition in the family wanting to know the risks to themselves or their children
  • a person worried about a family history of cancer, who wants to know if they are at increased risk, and to discuss their options
  • parents of a child with medical or learning difficulties where a genetic condition may be present, wanting an expert assessment.

In some cases, after taking a good family history and/or examining appropriate family members, it may be possible to give good advice without any further testing. In other cases, no testing may be available for the condition under consideration.

However, where testing is appropriate, the pros and cons are explained to the patient carefully before they make an informed choice. Non-directive counselling is at the core of clinical genetic practice.

Find out more at the clinical genetics society website


2.How does genetic predisposition interact with environmental factors to produce problems such as cancer or blood diseases?

Almost every medical condition will have some degree of genetic/environmental interaction. For example, in women with a BRCA1 mutation leading to a high lifetime risk (up to 80 per cent) of breast cancer, not everyone in a family will get cancer, even though they share exactly the same mutation. Similarly, people affected by Mendelian conditions, like cystic fibrosis or sickle cell disease, will have the disease in varying degrees of severity.

Of course, we count on at least one environmental factor having an effect on genetic predispositions ­ medical interventions!

3.What are the commonest conditions GPs should think of referring to a geneticist?

Common reasons for referral are spelled out in question 1, and often the reason for referral will be to try to make a diagnosis of an unknown condition. Because there is such a large number of rare conditions, this leads to an apparent paradox: rare conditions are collectively common.

Most GPs will have a few patients with rare disorders. So rather than think of a list of conditions to refer to genetics, it may be better to think of common reasons to refer. The unique contributions which genetics services can make are in:·

  • familiarity with rare disorders
  • access to genetic tests
  • ability to take a 'family-centred' view of a problem.

But as a rule of thumb, if in doubt, phone to ask. A directory of UK genetic centres can be found here.

4. How many members in a family need to be affected by colonic cancer before we refer patients for screening colonoscopy and at what age should this be done?

As colorectal cancer affects about one person in 30, familial clusters are bound to occur by chance. Most colorectal cancer cases are probably not due to genes conferring high risk.

However, in about 2-3 per cent of cases, a predisposition gene is present. Published criteria exist for recognising these high-risk colorectal families ­ the Amsterdam criteria (a research-based gold standard) and the St Marks criteria.

The age of screening depends on the level of risk and likely cause, and can range from colonoscopies commencing in the teens for familial polyposis coli to one colonoscopy at 35 and another at 55 for those at moderate risk of hereditary non-polyposis colon cancer (HNPCC).

5. Is polyposis coli a distinct condition or are there degrees of risk in patients who have multiple polyps?

Yes, adenomatous polyposis coli (APC, also known as familial adenomatous polyposis ­ FAP) is a genetically distinct condition due to mutations in the APC gene on chromosome 5.

It is clinically distinct, with colonic polyps commencing in the second decade, progres-sing to colons carpeted with hundreds of polyps by early adulthood and a virtual 100 per cent risk of colorectal cancer by age 40.

Other genetic predispositions to colorectal cancer include hereditary non-polyposis colon cancer which does not present with florid polyposis, and the recently described (2003) recessively inherited MYH colon cancer susceptibility gene.

6. What are the current best tests to screen for likely risk of breast cancer in the future?

The best screening test for assessing risk of breast cancer is a three-generation family history with corroborated diagnoses on affected relatives. Once the information has been obtained, risk can be assessed using the NICE guidelines. In cases where there is uncertainty, phone your regional genetics service for advice.

6. At what level of genetic risk is bilateral mastectomy indicated?

Genetic risk is not the only factor in considering this option ­ personal preference of the patient is very important, and her perception of the risks and benefits of all options are vital. But as a general rule this is usually considered in cases where a woman is known to carry a BRCA1 or BRCA2 mutation, which would confer a lifetime risk of up to 80 per cent of breast cancer. Increased risk of ovarian cancer also needs to be considered.

7. How should we counsel parents who have one child with cystic fibrosis and who wish to have a second pregnancy?

Since cystic fibrosis is inherited as a recessive trait, parents of one affected child must each be carriers of a CF mutation (assuming paternity is correctly assigned). They will therefore have a 25 per cent chance of each future pregnancy being affected by CF.

The parents need to be made aware of this, and potential future options such as pre-natal diagnosis discussed. If prenatal diagnosis may be considered in the future, it is important to identify the mutations in the affected child prior to the next pregnancy.

If a rare mutation is responsible, this may take several months to identify. Aunts and uncles of the affected child (the parents' siblings) will each have a 66 per cent of being carriers, and may wish to seek genetic counselling and discuss testing of themselves and their spouses.

8. Can genetic testing help us to identify patients with haemochromatosis earlier?

This is a controversial question. Hereditary haemochromatosis, leading to iron overload and risk of cirrhosis, diabetes and other complications is associated with two common mutations in the HFE gene, which can be easily tested. However, most people who carry these mutations do not go on to develop iron overload or clinical symptoms.

The British Society for Haematology guidelines recommend testing for iron overload (transferrin saturation and ferritin) but not mutation analysis as first-line investigation in symptomatic individuals.Mutation analysis is recommended as a confirmatory test in those with biochemically confirmed haemochromatosis.

First-degree relatives of clinically affected patients should be counselled about their risks and offered testing for iron overload and mutation analysis

.9. Private laboratories are increasingly offering genetic testing of various types and in some cases employers are actually encouraging it. How should GPs advise patients when they ask if they should have this done?

Genetic tests for some well-established genetic conditions, such as cystic fibrosis or breast and ovarian cancer susceptibility, are well validated, and have an important place in management of selected patients.

It is probable in the next three to five years that it will become possible to define genetic risk factors for commoner conditions such as diabetes and Alzheimer's disease.However, until large-scale clinical/genetic associations studies are conducted, tests based on early studies are premature and unlikely to provide robust risk information that clinical decisions could be based upon.

Some companies that provide a genetic risk analysis also recommend dietary supplements, which they sell to clients. The scientific basis of these recommendations is doubtful at best.

10. Which problems are likely to be first to benefit from gene transfer and how far off is it? Could it help in sickle cell and thalassaemia?

Gene therapy has been a 'holy grail' of gen-etic medicine for two decades. Unfortunately early optimism has not been fulfilled, as the barriers to integrating working genes in the correct tissues without complications has proved much harder than originally hoped.But clinical trials have been conducted; in particular, the first successful gene therapy was conducted at Great Ormond Street in 2005 on boys affected by ADA deficiency severe combined immunodeficiency

11.What are the potential ethical problems when patients undergo 'genetic testing'?

Genetics is not unique in dealing with ethical issues, but some of the specific issues are particular to genetics. The main features of genetic information which lead to ethical problems are that it is lifelong, shared between individuals and perceived to be highly predictive. Examples include the conflicts of interests that can arise in testing children, or testing one relative where the result may provide information on another.

  • Phil Zack is geneticist and project manager for GenePool (National Electronic Library for Genetics) ­ he is also specialist registrar in clinical genetics at Guy's and St Thomas' Hospital London
  • Competing interests none declared

What I will do now

Dr Peter Stott responds to the answers to his questions

  • The answers confirm that my knowledge of this subject is primitive.
  • The topic has advanced so much since I was at medical school that there is no way I can adequately answer even my own questions ­ even though I am doing my best for patients on a daily basis.
  • Few patients currently ask for genetic advice, but that does not mean to say that more will not seek it in the future.
  • If we are to offer patients adequate support, then GPs will either need to attend heavy-weight educational courses, or the NHS will need to offer GPs a much more comprehensive referral service. Either way, this is a rapidly developing topic that we cannot afford to neglect.

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