Background: Newborn jaundice affects 60-80% of newborn infants, and much effort goes into preventing the rare complication of bilirubin neurotoxicity evidenced as either severe or subtle bilirubin encephalopathy. We believe that genetics plays a significant role in modulating the risk of neurotoxicity in jaundiced infants. The lack of a monogenetic source for this risk leads us to believe that, like many diseases, the progression to a disease state is dependent upon an overall decrease in the functionality of one or more essential genetic pathways. In other words a “load” is placed on a key pathway or pathways in the form of multiple genetic variants that combine to create a vulnerable phenotype. The idea of epistatic interactions creating a pathway genetic load affecting the outcome to a specific insult has been previously reported (Huebinger, Garner et al. 2010). Hypothesis: We hypothesize that the pathway genetic load score will help explain the genetic background of complex diseases such as bilirubin encephalopathy and could be the key to understanding why there are wide ranges of outcome severity in these types of diseases. However, the difficulty in utilizing this method is in the identification of the key pathway(s), genes and variants that can be associated with increased risk. To that end we are proposing to use bilirubin encephalopathy as a first test in the development of methods to identify and confirm the factors that will contribute to a predictive pathway genetic load score. Specific Aim I: Sequence the whole exome of individuals exposed to high levels of bilirubin with neurologic dysfunction (n = 5) and without neurological dysfunction (n=5). Specific Aim II: Sequence the whole exome of individuals with low to moderate levels of bilirubin with neurological dysfunction (n= 5) and without neurological dysfunction (n=5). Specific Aim III: Identify single nucleotide polymorphisms (SNPs) likely to impact gene and pathway function in key pathways and calculate a pathway genetic load score for especially resistant (sequenced in specific aim I) and especially sensitive (sequenced in specific aim II) individuals. We will then statistically assess the ability of the bilirubin encephalopathy pathway genetic load scores to predict negative outcomes of patients exposed to various levels of bilirubin. Relevance: If successful, we anticipate that this method could be useful for improving the care of jaundiced newborns by screening the genetic backgrounds of newborns for risk level. Importantly, this method would also be useful in uncovering basic knowledge about this and numerous other polygenetic diseases whose genetic source is impossible to discern through traditional means such as a genome wide association study. This initial pilot study will serve as support for future grant applications aimed at expanding the sample size of this group and/or expanding into other neurological diseases with a complex genetic background. This project will also foster increased collaboration between the Center for Pediatric Genomic Medicine and the division of neurology whose patient base contains a high percentage of diseases and disorders with unknown and novel genetic backgrounds in need of further research.

2016-01-01

2017-01-01