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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.
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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).
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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.
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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 ...