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Multifactorial (Complex) Inheritance

by David N. Finegold, MD

Expression of many traits may involve multiple genes. Many such traits (eg, height) are distributed along a bell-shaped curve (normal distribution). Normally, each gene adds to or subtracts from the trait independently of other genes. In this distribution, few people are at the extremes and many are in the middle because people are unlikely to inherit multiple factors acting in the same direction. Environmental factors also add to or subtract from the final result.

Many relatively common congenital anomalies and familial disorders result from multifactorial inheritance. In an affected person, the disorder represents the sum of genetic and environmental influences. Risk of the occurrence of such a trait is much higher in 1st-degree relatives (siblings, parents, or children who share, on average, 50% of the affected person’s genes) than in more distant relatives, who are likely to have inherited only a few high-liability genes.

Common disorders with multifactorial inheritance include hypertension, coronary artery disease, type II diabetes mellitus, cancer, cleft palate, and arthritis. Many specific genes contributing to these traits are being identified by using the most sensitive genetic tests available (called next-generation sequencing—see Genetic Diagnostic Technologies) to test people with and without the traits for mutations. Genetically determined predisposing factors, including a family history and specific biochemical pathways often identified by molecular markers (eg, high cholesterol), can sometimes identify people who are at risk and are likely to benefit from preventive measures.

Multigenic, multifactorial traits seldom produce clear patterns of inheritance; however, these traits tend to occur more often among certain ethnic and geographic groups or among one sex or the other.

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