• Multifactorial inheritance refers to the pattern of inheritance of common health problems and rarer conditions caused by a combination of both genetic and other factors that may include internal factors such as ageing and exposure to external environmental factors such as diet, lifestyle, and exposure to chemicals or other toxins
• Multifactorial conditions have in common that they do not always develop despite the suggested presence of a faulty gene(s)
• The inherited faulty gene(s) make the person predisposed ie. at increased risk for developing the condition but unless other factors are present, the condition may never develop at all
• It may be possible to determine if family members are at risk for a particular multifactorial condition by examining their family health history and discussing it with their doctor
• Having one or more biological relatives who have been affected by a condition, particularly at a younger than expected age, is an indication that family members may be at risk of also developing that condition or passing it on to the next generation
• This can lead to the use of early detection tests and preventative strategies in which the triggering factors, if known, are avoided
• In the majority of cases, the pattern of inheritance of the faulty gene causing the susceptibility is autosomal dominant inheritance; eg. inherited predisposition to breast cancer. Despite inheriting a faulty gene, breast cancer will still never develop unless other genes are made faulty over the woman's lifetime, and these may be triggered by other unknown factors. These factors are likely to be environmental, including factors in our physical and chemical environment as well as the impact of ageing
• For a very few conditions, these triggers have been identified and include lack of the vitamin folate in the developing baby's environment which is linked to the chance that the baby will have a neural tube defect such as spina bifida. Supplementation of a woman's diet with folate in pre-pregnancy and in early pregnancy can significantly reduce the chance of a baby born with this condition. Such a preventative approach is only possible for those few conditions where the environmental trigger, or some of the triggers, have been identified
• Research is continuing to better understand the process that lead to a build-up of faulty genes in a person's body over their lifetime, causing the condition to develop. For those who are at increased risk for conditions due to an inherited predisposition, this may provide the means by which the condition is avoided altogether

As shown in Figure 11.1, the contribution from inherited genetic information to conditions that affect a person's growth, development and health is variable and ranges from conditions that:

• Are directly due to changes, present from birth, in the genetic information either in one or more of the 20,000 or so genes located in the nucleus (see Genetics Fact Sheet 1)
  • There are four 'traditional' patterns of inheritance that apply to the inheritance of the faulty gene(s) involved (see Genetics Fact Sheets 8, 9 & 10)
  • Risk estimation for the development of these genetic conditions in current or future family members is generally clear-cut although other unknown factors must be involved in the severity, or age of onset of the expression of their symptoms, as often there is variability even between family members
  • They are due to external factors in the person's physical and chemical environment and where genetic factors are not involved; eg. due to shared exposure to the same environmental factor such as poor quality air or water or poor nutrition
• Tend to 'run in the family' and an inherited faulty gene appears to be involved, but the patterns of inheritance are less predictable than expected. In these conditions the person's genetic make-up makes them susceptible (predisposed) to develop the condition but other factors need to be present for the condition to develop at all

Risk estimation for these genetic conditions to develop family members, is complex.

Complex patterns of inheritance also result with conditions where the faulty gene is located in the mitochondria or the nuclear faulty gene is not present in all the egg or sperm cells (germ cells) of a parent: the parent has a mixture of faulty and working gene copies in their germ cells. The complex patterns of inheritance for conditions arising from:

• Faulty mitochondrial genes is discussed in Genetics Fact Sheet 12
• Mosaicism for a faulty gene in the egg or sperm cells of parents in Genetics Fact Sheet 13

This Fact Sheet discusses conditions arising from the interaction of inherited changes in one or more genes with other factors in their internal or external environment.

As multifactorial conditions involve an inherited predisposition with an environmental trigger, an obvious preventive approach is to modify the known triggers in those individuals who are susceptible due to their family history.

For a very few conditions, these triggers have been identified.

• Lack of the vitamin folate in the developing baby's environment has been linked to the chance that the baby will have a neural tube defect such as spina bifida. Supplementation by folate in women pre-pregnancy and in early pregnancy can significantly reduce the number of babies born with this condition (see Genetic Fact Sheets 19 & 59)
• High dietary cholesterol is a factor in increased risk for cardiovascular disease (see Genetics Fact Sheet 54) and obesity has also been linked to increased risk for diabetes type 2 (see Genetics Fact Sheet 57) with exercise as an effective intervention

This approach is only possible for those few conditions where the environmental trigger, or some of the triggers, have been identified.

It is clear that for many common and rare conditions such as those listed in Table 11.1, simply inheriting one or more changed or faulty genes associated with a particular condition in some way is not enough for that condition to develop. The person's inherited genetic information may make them susceptible or predisposed to the condition but if other steps do not occur during their life then the condition will never develop.

The field of cancer genetics has provided some clues as to how the pathway works for some cancers to develop and this may be the model for other multifactorial conditions.

Knudson's '2-Hit Hypothesis'

In 1971, Alfred Knudson, a scientist, hypothesised that there was a relationship between inherited and new or sporadic cancers (not inherited). Knudson was aware that cancers arose because of genetic changes, and that these caused the genes critical for controlling cell growth and the division of cells to become faulty. Another way of looking at it is that these are normal 'cancer protection' genes that become faulty and can no longer do their usual job in the body (Figure 11.2 and Genetics Fact Sheet 47).

Dr Knudson proposed that the first cell of a rare tumour that developed in the eyes of children (retinoblastoma) underwent two different 'hits' that changed the information in both copies of a gene so that both gene copies were faulty (mutations).

Everyone has a gene (called the RB gene) that contains the information for the cells to produce a protein whose role is to prevent tumour growth (tumour suppressor protein) in the nerve-rich layers that line the back of the eyes (retina). In retinoblastoma a malignant tumour develops when both copies of the RB gene become faulty so that the tumour in the retina is not prevented.

RB occurs most commonly in children under the age of three and may be inherited or sporadic. He noted that RB could result from tumours (primary tumours) occurring in both eyes (bilateral) or only in one eye (unilateral), but the sporadic (non-inherited) forms of RB were always unilateral.

Most individuals with bilateral retinoblastomas had the familial form.

In other words, if two or more primary tumours occurred in the same person, it was more likely that all of the cells of the body had received the first 'hit' making the RB gene copy faulty at the time of conception. The child inherited one faulty copy of the RB gene and one working copy from each parent.

• As shown in Figure 11.2, the child is born with one of their RB gene copies faulty and then, over the first few years of their life, the other partner gene copy is also made faulty by some other unknown factor
• It was also very unlikely that each of these tumours arose independently at the same time due to independent chance 'hits' in the same gene out of the 20,000 or so genes in the human cells

Remarkably, this hypothesis was proposed in the early 1970s but it was not until 1987 that the identification of the retinoblastoma gene occurred and completely confirmed Knudson's hypothesis.

Knudson's theory is thought to not only apply to the development of inherited cancer in children, but to be one of the systems leading to other cancers that develop in later life, where both copies of a number of different 'cancer protection' genes must become faulty over the person's lifetime for the cancer to develop. (Figure 11.3).

It is likely that other complex conditions will be due to genetic and environmental interactions that lead to changes in the genetic information building up over the person's lifetime.

Other Genetics Fact Sheets referred to in this Fact Sheet: 1, 2, 8, 9, 10, 12, 13, 19, 21, 47, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59