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Although the genetics of most single-gene disorders are now quite well understood, these disorders account for a relatively small proportion of the total disease burden in the pediatric population compared with diseases that are thought to arise from the interaction of multiple genetic and environmental factors. Examples of the latter include neural tube defects, congenital heart defects, isolated cleft lip/palate, and clubfoot. Many multifactorial disorders are present at birth and are thus considered to be congenital malformations, but others, such as infantile autism and type 1 diabetes, typically present later in childhood. This section will review basic concepts relating to the genetics of multifactorial disorders, with emphasis on diseases that occur in the pediatric population.

Many quantitative traits, such as height, blood pressure, and IQ, exhibit a normal distribution in human populations, which is the consequence of multiple genetic and environmental influences on the phenotype (hence the designation multifactorial). Most of the diseases to be considered in this chapter, however, are either present or absent in the individual. There is an underlying liability distribution for these disorders, which follows the familiar bell-shaped curve. If an individual has enough liability factors to exceed a threshold, then that person is affected with the disorder (Fig. 171-1).

Figure 171-1.

The liability distribution for a multifactorial disease. An individual must exceed a threshold on this distribution to be affected with the disease.

In some cases, the threshold may be higher in one sex than in the other. Pyloric stenosis is a classic example of a multifactorial disease that appears to follow such a sex-specific threshold model. This birth defect, in which a narrowing of the pylorus produces constipation, chronic vomiting, weight loss, and electrolyte imbalance, affects approximately 1 in 1000 females and approximately 1 in 200 males. This pattern indicates that the liability threshold is higher for females than for males. Accordingly, affected females should possess more liability factors than should affected males. Having more risk factors, affected females will be more likely to produce affected offspring. This prediction is borne out in Table 171-1, which shows that the recurrence risk is considerably higher for the offspring of affected females than for the offspring of affected males.

Table 171-1. Recurrence Risks for Offspring of Individuals Affected with Pyloric Stenosis

A similar pattern is seen in infantile autism, in which the male-to-female ratio is approximately 4:1. The threshold is thought to be higher for females than males in this multifactorial disorder, and one large study showed that the recurrence ...

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