The Impact of Genomics on Pediatric Research and Medicine

Abstract

In this review, we discuss some of the most recent developments in genomics research and their relevance to the field of pediatrics. In particular, we examine 3 major approaches that are being used to identify genetic correlates of disease: genome-wide association studies, copy number variation studies, and next-generation sequencing.In the past few years, these approaches have yielded major insights into the causes and pathophysiology of a wide range of diseases but are also constrained by certain limitations. This review provides an overview of the genomic landscape in complex pediatric disorders and sets the stage for translating new discoveries into clinical practice, the future of genomic medicine. 1150CONNOLLY and HAKONARSONIn this review, we provide a narrative of recent developments in genomics, with the aim of generating a broad overview of the field as a whole. We focus on the 3 main approaches (genome-wide association studies (GWAS), copy number variation analysis, and next-generation sequencing [NGS]) that have been instrumentalinpropellingthefieldforward. GENOME-WIDE ASSOCIATION STUDIESGWAS use single nucleotide polymorphisms (SNPs) to identify and compare allele frequencies in target populations, typically by using either case-control or family-based designs. The former is the most common because it is conducive to large-scale recruitment and is not constrained by limits on the numbers of controls. The latter has advantages in terms of controlling for population stratification and the types of analysis that are possible. GWAS use microarrays to tag up to several million SNPs at once, which gives broad coverage of genic and nongenic regions. The approach is hypothesis-independent, and all SNPs carry equal weight during statistical analyses. When a significant difference in SNP frequency is observed between cases and controls, we infer a difference in the underlying genomic locus, which may affect gene expression or regulation. Because of the large number of comparisons being made, most GWAS require large numbers of patients and controls to achieve requisite statistical power, and sample sizes in excess of several thousand are the norm. A major advantage of the approach is its applicability to complex disease, where numerous loci may be implicated as causal factors.GWAS are constrained by the fact that they can only examine SNPs found in relative abundance in the population of interest; generally SNPs with a population frequency of ∼5% or greater. A major assumption, therefore, is that the variants under investigation are common. By extension, a second assumption is that the phenotype of interest is caused by the cumulative result of many small-effect variants. These assumptions constitute the so-called common disease, common variant model, 1 which has successfully identified variants in many complex disorders, some of which are reviewed here. For diseases caused by rare variants, including many Mendelian syndromes, GWAS are underpowered, and sequencing approaches are required, either of lin...

Copy number variation analysis in the context of electronic medical records and large-scale genomics consortium efforts

“…Custom probes offer greater coverage of non-SNP sites, and can offer high sensitivity, particularly with regard to breakpoint resolution ( Haraksingh et al, 2011 ). While conventional (i.e., non-custom) SNP arrays offer less specificity, they nevertheless represent a cost-effective option for characterizing CNVs and have been successfully applied to a wide range of phenotypes to date ( Connolly and Hakonarson, 2012 ).…”

Metabolomic Analysis of the Effect of Postnatal Hypoxia on the Retina in a Newly Born Piglet Model

“…Therefore, specific molecular modifications on DNA, RNA, proteins or metabolite levels can be useful biomarkers. Despite considerable efforts focused on genomics and proteomics, molecular biomarkers found to be useful in the diagnosis of perinatal asphyxia are lacking [9], [10]. The most widely employed markers of brain damage after a hypoxic episode include S100B, neuron-specific enolase, activin A, adrenomedullin, Interleukin (IL)-1β and IL-6.…”

A Genomically Informed Education System? Challenges for Behavioral Genetics

“…It is estimated that ~4 million infants in the U.S. undergo newborn screening each year, and while current programs focus on metabolic, hematologic, and endocrine conditions for which early prevention or intervention are available, 8 there are ongoing initiatives to expand newborn screening programs to next-generation sequencing. 9 The number of children who are tested for various neuropsychiatric syndromic conditions, including those associated with intellectual disabilities, is on the rise, 10 as is the number of children who participate in studies that utilize next generation sequencing technologies 11 and are offered at least some return of results. 12…”