The National Children's Study--a proposed plan.

With its coordinated longitudinal biologic, environmental-exposure, and phenotypic data and samples, the National Children's Study is aiming to provide an important resource for understanding children's growth, development, and health.

Personalized genomic information: preparing for the future of genetic medicine.

The falling cost of sequencing means that we are rapidly approaching an era in which access to personalized genomic information is likely to be widespread. Here, four experts with different insights into the field of genomic medicine answer questions about the prospects for using this type of information. Their responses highlight the diverse range of issues that must be addressed - ranging from scientific to ethical and logistical - to ensure that the potential benefits of personal genomic information outweigh the costs to both individuals and societies.

Finding the missing heritability of complex diseases.

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

We don't know what we don't study: the case for research on medication effects in pregnancy.

This Commentary addresses issues related to exposures to teratogens and makes the case for increased research into the safety of medication usage during pregnancy for mothers and fetuses. Not only are medications commonly used during pregnancy, but evidence points to an increasing prevalence and number of drug exposures experienced by the embryo or fetus, particularly during the critical first trimester of pregnancy. Although the first trimester represents a particularly vulnerable period of organogenesis, exposures during other gestational time periods may also be associated with deleterious outcomes. In addition to the changing (and in many cases unknown) risks to a developing fetus, other challenges to studying medication exposures and their effects during pregnancy include the dramatic changes in physiology that occur in pregnant women and the ethical dilemmas posed by including this vulnerable population in randomized controlled trials of safety and efficacy. However, without adequate knowledge of the pharmacokinetics, pharmacodynamics, efficacy, and safety of medication use in pregnancy, women may be under-dosed to minimize exposure or not treated at all, resulting in inadequate treatment and potential harm to the mother and her baby. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is undertaking studies on medications and teratogenic exposures during pregnancy, including alcohol, maternal diabetes, oral hypoglycemic agents, and antiviral medications, through several of its research networks. Although this is a start, there is a critical need for further research on medications used during pregnancy, especially their effects on both the mother and her developing child.

Commentary: trailblazing a research agenda at the interface of pediatrics and genomic discovery--a commentary on the psychological aspects of genomics and child health.

Unprecedented advances in human genome science are underway with potential to benefit public health. For example, it is estimated that within a decade, geneticists and epidemiologists will complete a catalog of the majority of genes associated with common chronic diseases. Such rapid advances create possibilities, if not the mandate, for translational research in how best to apply these and other anticipated discoveries for both individual and population health benefit. Driving these discoveries are rapid advances in infrastructure (e.g., the International HapMap Project to catalog human genetic variation; http://www.hapmap.org), analytical methods, and technology. This expansion in capabilities quickly has taken us from a genetics paradigm-where the influence of individual genes on health outcomes is paramount, to a genomics paradigm-where the complex influence of individual genes is considered in concert with each other and with environmental exposures on health outcomes. We discuss these and similar groundbreaking discoveries with an eye toward understanding their importance to child health and human development, and the role of behavioral science research conducted at the interface of pediatrics and genomic discovery.

A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome.

Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities, has several features in common with hand-foot-genital syndrome (HFGS), including hypoplastic first digits and hypospadias. The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2(nd) toes with absent nails, suggests that it represents a distinct entity. HFGS is caused by mutations in the HOXA13 gene. We have therefore re-investigated the original Guttmacher syndrome family, and have found that affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L), which arose on an allele already carrying a novel 2-bp deletion (-78-79delGC) in the gene's highly conserved promoter region. This deletion produces no detectable abnormalities on its own, but may contribute to the phenotype in the affected individuals. The missense mutation, which alters a key residue in the recognition helix of the homeodomain, is likely to perturb HOXA13's DNA-binding properties, resulting in both a loss and a specific gain of function.

Genetic testing and psychology. New roles, new responsibilities.

Advances in genetics and genetic testing promise to catalyze a fundamental change in the practice of medicine. Psychologists have much to offer as psychotherapists, researchers, educators, and policymakers to a society heavily influenced by the genetic revolution. To make the most of new opportunities available to mental health professionals in genetics, psychologists must know basic genetic principles and learn what is new about 21st-century genetics. The core competencies for all health professionals developed by the National Coalition for Health Professional Education in Genetics are related in this article to the significant roles psychologists can play in helping individuals with genetic concerns to cope with vulnerability, optimize family interaction, and improve health behaviors.

Genomics, personalized medicine, and pediatrics.

Genomic discoveries are advancing biomedicine at an ever-increasing pace. Pediatrics is near the epicenter of these discoveries, which are revising our understanding of the genome and its function. Since the completion of the Human Genome Project in 2003, dramatic reductions in the cost of genotyping, and more recently sequencing, have permitted the study of the genomes of a great number of species as well as humans. These studies have led to insights on gene regulation and the complex interplay of factors responsible for normal development and biology. Study of single-gene disorders has greatly benefited from the genomics revolution and tests are now available for well over 2000 Mendelian conditions; availability of these tests are changing screening and diagnosis paradigms for rare conditions. Genomics is also yielding an increased understanding of common conditions such as diabetes, obesity, asthma, cancers, and mental health conditions. Personalized medicine, an approach to care in which an individual's genomic information is used to help tailor interventions to maximize health outcomes, is rapidly becoming a reality for a variety of conditions. Though challenges remain in translating new genomic insights into improved patient health, today's pediatricians and their patients will increasingly benefit from this watershed moment in the biological sciences.