Multifactorial traits that have a normal distribution in the population are termed continuously variable. A measurement that is more than two standard deviations above or below the population mean is considered abnormal. Continuously variable traits tend to be less extreme in the ofspring of afected individuals, because of the statistical principle of regression to the mean.
Some multifactorial traits do not appear until a threshold is exceeded. Genetic and environmental factors that create propensity or liability for the trait are themselves normally distributed, and only individuals at the extreme of the distribution exceed the threshold and exhibit the trait or defect. Phenotypic abnormality is thus an all-or-none phenomenon. Examples include cleft lip-palate and pyloric stenosis.
Certain threshold traits have a clear male or female predominance. If an individual of the less common gender has the characteristic or defect, the recurrence risk is greater in his or her ofspring (Fig. 13-10). An example is pyloric stenosis, which is approximately four times more common in males (Krogh, 2012). A female with pyloric stenosis has likely inherited more predisposing genetic factors than are necessary to produce the defect in a male, and the recurrence risk for her children or siblings is thus higher than the expected 3 to 5 percent. Her male siblings or male ofspring would have the highest liability because they not only will inherit more than the usual number of predisposing genes but also are the more susceptible gender.
he recurrence risk for threshold traits is also greater if the defect is severe. For example, the recurrence risk after the birth of a child with bilateral cleft lip and palate is approximately 8 percent, but it is only about 4 percent following a child with unilateral cleft lip alone.
Structural cardiac anomalies are the most common birth defects, with a birth prevalence of 8 cases per 1000. More than o.�c 5.
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FIGURE 13-10 Schematic example of a threshold trait, such as pyloric stenosis, which has a predilection for males. Each gender is normally distributed, but at the same threshold, more males than females will develop the condition.
100 genes believed to be involved in cardiovascular morphogenesis have been identiied, including those directing production of various proteins, protein receptors, and transcription factors (Olson, 2006; Weismann, 2007).
he risk of having a child with a cardiac anomaly is approximately 5 to 6 percent if the mother has the defect and 2 to 3 percent if the father has the defect (Burn, 1998). Selected left-sided lesions, including hypoplastic left heart syndrome, coarctation of the aorta, and bicuspid aortic valve, may have recurrence risks four-to sixfold higher (Lin, 1988; Lupton, 2002; Nora, 1988). Observed recurrence risks for specific cardiac malformations are listed in Table 49-4 (p. 953).
These disorders are also classic examples of multifactorial inheritance. Development of neural-tube defects (NTDs) may be influenced by hyperthermia, hyperglycemia, teratogen exposure, ethnicity, family history, fetal gender, and various genes. Selected risks are more strongly associated with the specific defect location. Hyperthermia has been linked with anencephaly risk; pregestational diabetes with cranial and cervicalthoracic defects; and valproic acid exposure with lumbosacral defects (Becerra, 1990; Hunter, 1984; Lindhout, 1992). Sonographic features ofNTDs are described in Chapter 10 (p. 192), their prevention with folic acid is discussed in Chapter 9 (p. 169), and fetal therapy for myelomeningocele is reviewed in Chapter 16 (p. 319).