|Close relatives （up to third-degree） tend to resemble each other with respect to a number of quantitative or measurable characteristics （eg, height, weight, size and shape of nose, facial features, BP, intelligence）. Many traits are distributed along a bell-shaped curve, a phenomenon that is compatible with determination of the trait by several genes. Each gene adds to or subtracts from the trait and acts in an additive manner independent of other genes. Few persons are at the extremes of the distribution and many are in the middle, because a person is unlikely to inherit many factors acting in the same direction. Environmental factors, each adding to or subtracting from the final result, will also produce a normal distribution.
|Many relatively common congenital anomalies and familial diseases do not follow expectations for single-gene （Mendelian） inheritance. More likely, these conditions result from multifactorial inheritance; a threshold separates the affected person from the unaffected person. The affected person is predisposed to the condition, representing the sum of genetic and environmental influences. Thus, the risk of expression of such a trait in first-degree relatives （siblings and children）, who share 50% of the affected person's genes, is relatively high. The risk in more distant relatives, who are likely to inherit only a few high-liability genes, is much lower.
|For example, neural tube defects （NTDs--anencephaly, spina bifida, encephalocele, myelomeningocele） usually have multifactorial causes, although they also have many specific known single-gene, chromosomal, and environmental causes. In the North American white population, NTDs occur with a combined incidence of about 1.5/1000 live births. Unaffected parents of an affected infant are thought to carry many high-liability genes and have about a 1/30 （3%） chance of having a second affected offspring. Similarly, a parent with a multifactorial NTD has a 3 to 4% chance of having an affected child. In the rare instance when a couple has had two affected children, the risk for a third increases to 7 to 8%.
|Environmental factors play a role in multifactorial inheritance. The incidence of NTDs approaches 1/100 in western parts of the United Kingdom, yet when persons from a high-risk area emigrate to North America, their risk falls but remains higher than that of the North American population. Also, 50 to 70% of NTDs can be prevented by maternal folic acid supplementation （400 µg/day） 1 mo before conception to 3 mo after conception. Although maternal folic acid deficiency plays a major role, it is not the only environmental cause of NTDs.
|Other examples of multifactorial inheritance, with similar risks for siblings and offspring of affected persons, are congenital anomalies of the heart, idiopathic epilepsy （petit or grand mal）, and most cases of cleft lip with or without cleft palate. In congenital pyloric stenosis, the male:female ratio is 5:1, suggesting that the threshold for females is higher. Thus, compared with a male, a female requires more potent liability genes to develop the condition, has more affected siblings, and has a greater risk of having affected offspring.
|Attention is being focused on common adult disorders with multifactorial causes （eg, hypertension, arteriosclerotic heart disease, diabetes mellitus, cancer, arthritis）. Many specific genes are being found. Genetically determined predisposing factors, including a family history and biochemical and molecular parameters, can identify persons at risk who would most likely benefit from preventive measures.