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Chapter 1. Genetics of Neonatal Jaundice

Jon F. Watchko; Zhili Lin

Neonatal hyperbilirubinemia and resultant jaundice are common,1,2 affecting up to ˜80% of newborns.1 Although generally a benign postnatal transitional phenomenon, a select number of infants develop more significant and potentially hazardous levels of total serum bilirubin (TSB) (Table 1-1)3,4 that may pose a direct threat of brain damage.3,5,6 Numerous factors contribute to the development of hyperbilirubinemia including genes involved in: (i) the production of bilirubin from heme; (ii) the metabolism of bilirubin; and (iii) heritable conditions that may reduce red blood cell (RBC) life span and predispose to hemolysis, thereby increasing the bilirubin load7–17 in neonates. The genetics of neonatal hyperbilirubinemia is the focus of this chapter.

Table 1-1. Estimated Occurrence of Neonatal Hyperbilirubinemia Severity
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Table 1-1. Estimated Occurrence of Neonatal Hyperbilirubinemia Severity
TSB (mg/dL) aProposed DefinitionEstimated Occurrence
≥17.0 (291 μmol/L)Significant˜1:10
≥20.0 (342 μmol/L)Severe˜1:70
≥25.0 (428 μmol/L)Extreme˜1:700
≥30.0 (513 μmol/L)Hazardous˜1:10,000

aTSB, total serum bilirubin.

Adapted from Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol. 2004;24:650–662, with permission from Macmillan Publishers Ltd, copyright 2004.

In contrast to fully penetrant genetically dominant conditions or those that are mainly environmentally derived, severe neonatal hyperbilirubinemia (TSB >20 mg/dL [342 μmol/L])3,4 is frequently manifested as a pediatric complex trait or disorder. The term complex in this context infers the condition is: (i) prevalent (>1% of neonates);3,4 (ii) multifactorial;16,17 and (iii) polygenic16,17 (Figure 1-1).18 In fact, severe neonatal hyperbilirubinemia is often marked by: (1) etiologic heterogeneity; (2) key environmental influences; and/or (3) the interaction of multiple gene loci, which individually show relatively limited effects, but with each other and nongenetic factors7–17,19—a contributing role to hyperbilirubinemia risk.

Figure 1-1.
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The relationship between genetic load and environment in the development of disease is shown in this schema.18 An etiologic continuum from strictly genetic, through polygenic–multifactorial, to largely environmental is observed. Severe neonatal hyperbilirubinemia is characteristically a polygenic–multifactorial trait. (Reproduced from Bomprezzi R, Kovanen PE, Martin R. New approaches to investigating heterogeneity in complex traits. J Med Genet. 2003;40:553–559, with permission from BMJ Publishing Group Ltd.)

Characterizing the genetics underlying complex traits is fraught with challenges.18 Several lines of epidemiologic evidence,20 however, support the assertion that genetic contributors are clinically relevant modulators of neonatal hyperbilirubinemia. These include: (i) the clinical significance of a positive family history; (ii) twin studies; (iii) the impact of genetic heritage on hyperbilirubinemia risk; and (iv) male/female differences. This information will be briefly reviewed before an analysis of known icterogenic and candidate genes involved in the control of ...

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