Informed consent: genetic risk and genetic counsel

Many women with a family history of breast cancer elect for a radical double mastectomy, rather than run the genetic gauntlet.

Not every woman carrying high-risk alleles of genes like BRCA1 and BRCA2 develops breast cancer, but Professor Ingrid Winship says many would prefer to spare their own daughters the psychological impact of living with its spectre.

By screening embryos produced by in vitro fertilisation for BRCA1 and BRCA2 mutations before implantation, molecular geneticists can help affected families eliminate the risk to later generations.

Winship, an invited speaker at this year's Clinical Research Excellence Conference (CRX07) conference in Melbourne, taking place this weekend, was last year appointed to the inaugural chair of adult clinical genetics at the University of Melbourne.

Despite the ethical concerns surrounding genetic testing before and during pregnancy, she says that in two decades as a counsellor and clinician, she has never been asked to terminate a pregnancy on grounds of genetic risk.

"But many are interested in the possibility of selecting embryos that do not carry mutations that would predispose them to develop cancer," she says.

Born in South Africa at educated at the University of Cape Town, Winship moved to New Zealand in 1994 to take up an appointment as a senior lecturer in clinical genetics at the University of Auckland.

She subsequently became Dean of the Faculty of Medical and Health Sciences, and then was appointed professor of the new chair of clinical genetics. In 2006 she moved to the University of Melbourne.

Winship believes pre-implantation diagnosis could have an "enormous impact" on adult-onset genetic disorders.

"We've seen an absolute revolution [in human genetics], culminating in the human genome project. We're taking all that stuff and seeing what is feasible, practical, or might have utility in the clinic.

"If we're going to develop new practices, they need to be evidence-based, to ensure they will make a difference."

Many adult-onset disorders, like type 2 diabetes, cardiovascular disease and cancers are genetically complex, and strongly influenced by lifestyle factors, so they are not amenable to pre-implantation diagnosis.

Winship focuses on monogenic disorders - while environmental factors also influence their expression, counsellors can advise individuals how to modify their lifestyles to reduce their risk.

Evidence-based strategies

Familial cancers are genetically complex, but Winship says a subset of cancers are strongly influenced by particular alleles of single genes - the influence of BRCA1 and BRCA2 in breast cancer being an example.

Hereditary polyposis, a strong predisposing factor for bowel cancers, is due to defective alleles of genes coding for DNA repair enzymes, which normally repair mismatch errors when chromosomes are replicated in dividing cells. Winship says people with such mutations are at high risk of developing bowel cancer in early adulthood.

The same mutations predispose females to gynaecological cancers. "I've been working in this area for some time, to develop evidence-based strategies to modify risk."

Winship says such strategies are applicable to many other disorders that manifest in adulthood, or which appear at stages in a patient's life where they are particularly vulnerable, such as in pregnancy.

Winship counsels individuals at risk of hereditary complications of cardiovascular disease, such as hypertrophic cardiomyopathy, and Marfan syndrome - a collagen disorder that can result in sudden, fatal rupture of the aorta.

Haemorrhagic telangiectasia, which involves the formation of spider-web-like fine blood vessels on the skin, causes nosebleeds in children, but can predispose individuals to dangerous malformations of the arteries and veins in the lungs, brain and liver in adulthood.

Winship says she and her staff aim to provide cradle-to-grave counselling - "We're not just concerned with perinatal care. We're also interested in paediatric and adult care, and what happens after death, in affected descendants."

Whole genome

Winship is unsurprised and undaunted by the "junk DNA" revolution, with its revelation that some inherited disorders may involve polymorphisms lying outside the protein-coding exons of genes, in introns or tracts of inter-genic DNA, that code for small RNA molecules that regulate gene expression.

"Like many geneticists, I always knew that the whole genome would have a point. There's no surplus in nature, and although we used to talk about junk in the old days, I've never been able to get my head around the idea that it was anything but important.

"Every new piece of information we get is valuable, if it makes it easier for use to extend people's lives. It makes our clinical work easier in some respects, but harder in others, because it presents options we didn't have before. Before we had these options, people didn't have to make a choice.

"There have certainly been changes and trends in the way people feel about genetic information. It's very important that the community of geneticists and genetic counsellors protect people's right to make informed choices."

Winship said genetic tests capable of identifying susceptibility to Huntington's disease, and even to predict the approximate age of onset, was a case in point.

In the absence of an effective treatment or remedy, many people had decided not to undergo genetic testing.

"Empowerment is a strategy in itself - people who choose not to have the knowledge may also be interested in preventing consequences where genetics plays a role. If you know what the risks are, you have a better chance of preserving the health of healthy people.

Psychosocial effect

Winship is interested in the psychosocial impact of genetic counselling. Working in Auckland 12 years ago, she began a project to explore the cultural and spiritual issues surrounding genetic counselling in Maori people, whose strong spiritual sense influences their views towards genetics and genetic counseling.

She says the ownership of genes is complex issue. "Do you own your genes, or are they collectively owned by you, your forebears and future generations? It's a hard one.

"If you've inherited a mutant allele from a parent, your children may be affected. It's not just mutated genes - all genes are owned collectively."

Winship says people have a strong intuitive understanding of the importance of genetics - "When they see a newborn, they will say it has its father's nose, or mother's mouth."

This intuitive understanding demands a strong, ethical approach to counselling, to minimise the risk that the counselor may unwittingly let highly personal information slip - such as when testing detects that a child's father is not its biological one.

"When we do any kind of genetic counselling, we always get informed consent, and we contract to look only at one gene."