Newborn screening system: Safety, technology, advocacy.

Newborn screening (NBS) is more than 50 years old and has proven to be a powerful and successful public health system. NBS must be regarded as a system and not simply as a test. We need to work as a community to improve the culture of safety for the NBS system and thereby to reduce the risk of babies being missed by the NBS system. Adding new technologies will not prevent system failures; that will require adherence to the culture of safety. Some have argued that every newborn should have their genome sequenced at birth and this sequencing could be part of NBS. However, NBS has depended on biomarker phenotypes throughout its history and our understanding of the relationships between genotype and phenotype is imperfect. Therefore, we should avoid being seduced by genomic sequencing technology and continue to focus on phenotypic biomarkers in NBS.

Explaining the Black-White Disparity in Preterm Birth: A Consensus Statement From a Multi-Disciplinary Scientific Work Group Convened by the March of Dimes.

In 2017-2019, the March of Dimes convened a workgroup with biomedical, clinical, and epidemiologic expertise to review knowledge of the causes of the persistent Black-White disparity in preterm birth (PTB). Multiple databases were searched to identify hypothesized causes examined in peer-reviewed literature, 33 hypothesized causes were reviewed for whether they plausibly affect PTB and either occur more/less frequently and/or have a larger/smaller effect size among Black women vs. White women. While definitive proof is lacking for most potential causes, most are biologically plausible. No single downstream or midstream factor explains the disparity or its social patterning, however, many likely play limited roles, e.g., while genetic factors likely contribute to PTB, they explain at most a small fraction of the disparity. Research links most hypothesized midstream causes, including socioeconomic factors and stress, with the disparity through their influence on the hypothesized downstream factors. Socioeconomic factors alone cannot explain the disparity's social patterning. Chronic stress could affect PTB through neuroendocrine and immune mechanisms leading to inflammation and immune dysfunction, stress could alter a woman's microbiota, immune response to infection, chronic disease risks, and behaviors, and trigger epigenetic changes influencing PTB risk. As an upstream factor, racism in multiple forms has repeatedly been linked with the plausible midstream/downstream factors, including socioeconomic disadvantage, stress, and toxic exposures. Racism is the only factor identified that directly or indirectly could explain the racial disparities in the plausible midstream/downstream causes and the observed social patterning. Historical and contemporary systemic racism can explain the racial disparities in socioeconomic opportunities that differentially expose African Americans to lifelong financial stress and associated health-harming conditions. Segregation places Black women in stressful surroundings and exposes them to environmental hazards. Race-based discriminatory treatment is a pervasive stressor for Black women of all socioeconomic levels, considering both incidents and the constant vigilance needed to prepare oneself for potential incidents. Racism is a highly plausible, major upstream contributor to the Black-White disparity in PTB through multiple pathways and biological mechanisms. While much is unknown, existing knowledge and core values (equity, justice) support addressing racism in efforts to eliminate the racial disparity in PTB.

Enabling Technologies for Personalized and Precision Medicine.

Individualizing patient treatment is a core objective of the medical field. Reaching this objective has been elusive owing to the complex set of factors contributing to both disease and health; many factors, from genes to proteins, remain unknown in their role in human physiology. Accurately diagnosing, monitoring, and treating disorders requires advances in biomarker discovery, the subsequent development of accurate signatures that correspond with dynamic disease states, as well as therapeutic interventions that can be continuously optimized and modulated for dose and drug selection. This work highlights key breakthroughs in the development of enabling technologies that further the goal of personalized and precision medicine, and remaining challenges that, when addressed, may forge unprecedented capabilities in realizing truly individualized patient care.

Metabolite flux: A dynamic concept for inherited metabolic disorders as complex traits.

In 2000 and 2001, we described factors that lead to the phenotypes of individuals with "simple," "single" gene disorders, like inherited metabolic disorders, being complex, multi-genic traits. These factors include functional thresholds, genetic and environmental modifiers, and systems dynamics, encompassing metabolic control analysis and scale-free, hub-and-spoke networks. This mini-review will consider topics influencing complexity developed in the ensuing nearly two decades, such as "synergistic heterozygosity" and "moonlighting proteins." There will be a focus on the value of the measurement of flux in evaluating the metabolome to ascertain phenotypic variability and the potential role of the gut microbiome in metabolomic flux. A point-of-care metabolomics tool, under development to improve the real time, inter-operative ascertainment of tumor margins and similar devices, will provide opportunities to improve acute care and ongoing management of individuals with inherited metabolic disorders.

Modifier genes: Moving from pathogenesis to therapy.

This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms. Since one of the goals of research on modifier genes and networks is to identify novel therapeutic targets, the challenges to patient access and compliance because of the high costs of medications for rare genetic diseases must be recognized. A recent article explored protective modifiers, including plastin 3 (PLS3) and coronin 1C (CORO1C), in spinal muscular atrophy (SMA). SMA is an autosomal recessive deficit of survival motor neuron protein (SMN) caused by mutations in SMN1. However, the severity of SMA is determined primarily by the number of SMN2 copies, and this results in significant phenotypic variability. PLS3 was upregulated in siblings who were asymptomatic compared with those who had SMA2 or SMA3, but identical homozygous SMN1 deletions and equal numbers of SMN2 copies. CORO1C was identified by interrogation of the PLS3 interactome. Overexpression of these proteins rescued endocytosis in SMA models. In addition, antisense RNA for upregulation of SMN2 protein expression is being developed as another way of modifying the SMA phenotype. These investigations suggest the practical application of protective modifiers to rescue SMA phenotypes. Other examples of the potential therapeutic value of novel protective modifiers will be discussed, including in Duchenne muscular dystrophy and glycerol kinase deficiency. This work shows that while we live in an exciting era of genomic sequencing, a functional understanding of biology, the impact of its disruption, and possibilities for its repair have never been more important as we search for new therapies.

Gestational Diabetes Associated with a Novel Mutation (378-379insTT) in the Glycerol Kinase Gene.

Glycerol kinase deficiency (GKD) is an X-linked inborn error of metabolism at the interface of fat and carbohydrate metabolism. We report a male patient with GKD and a novel insertion of TT in exon 5 at position 378 of the GK cDNA (378-379insTT). This resulted in a premature stop codon and 0.8% normal GK activity. The mother is a carrier for this mutation and had gestational diabetes requiring insulin during this pregnancy but not in her previous pregnancy. Given the association between GKD and type 2 diabetes mellitus, it is interesting that the mother had gestational diabetes while carrying an affected fetus. Therefore, GKD is another disease where there may be a maternal-fetal interaction based on genotype. Further investigations may help elucidate the role of GKD in the carrier mother's gestational diabetes. In addition, these studies will provide better-informed counseling to families with GKD regarding the risk to carrier females.

Greater risk of hospitalization in children with Down syndrome and OSA at higher elevation.

BACKGROUND: Children with Down syndrome (DS) are at high risk for OSA. Increasing elevation is known to exacerbate underlying respiratory disorders and worsen sleep quality in people without DS, but whether altitude modulates the severity of OSA in DS is uncertain. In this study, we evaluate the impact of elevation (≤ 1,500 m vs > 1,500 m) on the proportion of hospitalizations involving OSA in children with and without DS. METHODS: Merging the 2009 Kids' Inpatient Database with zip-code linked elevation data, we analyzed differences in the proportion of pediatric hospitalizations (ages 2-20 years) involving OSA, pneumonia, and congenital heart disease (CHD), with and without DS. We used multivariable logistic regression to evaluate the association of elevation with hospitalizations involving OSA and DS, adjusting for key comorbidities. RESULTS: Proportionately more DS encounters involved OSA, CHD, and pneumonia within each elevation category than non-DS encounters. However, the risk difference for hospitalizations involving OSA and DS increased disproportionately at higher elevations (DS: 16.2% [95% CI, 9.2%-23.2%]; non-DS: 0.1% [95% CI, -0.4% to 0.7%]). Multivariable estimates of relative risk indicate increased risk for hospitalization involving OSA at higher elevations for people with DS and in children aged 2 to 4 years or with two or more chronic conditions. CONCLUSIONS: At elevations > 1,500 m, children with DS and OSA have a disproportionately higher risk for hospitalization than children with OSA without DS. This finding has not been described previously. With further validation, this finding suggests the need for greater awareness and earlier screening for OSA and its complications in patients with DS living at higher elevations.

Fighting for the next generation: US Prematurity in 2030.

Preterm birth (PTB) is a serious problem, with >450 000 neonates born prematurely in the United States every year. Beginning in 1980, the United States experienced a nearly 3-decade rise in the PTB rate, peaking in 2006 at 12.8%. PTB has declined for 7 consecutive years to 11.4% in 2013, but it still accounts for 1 in 9 neonates born every year. In addition to elevated neonatal and infant mortality among those born preterm, many who survive will have lifelong morbidities and disabilities. Because of the burden of morbidity, disability, and mortality for PTB, as well as its impact more broadly on society, including excess annual costs estimated to be at least $26.2 billion by a committee for the Institute of Medicine, the March of Dimes initiated the Prematurity Campaign in 2003. In 2008 the March of Dimes established a goal of reducing the US PTB rate to 9.6% by 2020. However, the United States ranks extremely poorly for PTB rates among Very High Human Development Index (VHHDI) countries, subjecting untold numbers of neonates to unnecessary morbidity and mortality. Therefore, the March of Dimes proposes an aspirational goal of 5.5% for the 2030 US PTB rate, which would put the United States in the top 4 (10%) of 39 VHHDI countries. This 5.5% PTB rate is being achieved in VHHDI countries and by women from diverse settings receiving optimal care. This goal can be reached and will ensure a better start in life for many more neonates in the next generation.

Newborn screening: A complex system that requires a culture of safety.

As health care providers and organizations, we have a responsibility to examine our practices and systems for opportunities to improve quality and health outcomes. Today a critical opportunity exists in the newborn screening (NBS) system, which touches every one of the approximately 4 million babies born annually in the United States. This opportunity involves improving the quality of NBS by developing a culture of safety to prevent errors that in NBS represent missed babies and preventable morbidity and mortality. This commentary will explore the "culture of safety" for NBS, including the high reliability organization (HRO) paradigm and normal accident theory (NAT), which have been effective in reducing systems failures in other complex environments.

Development of catecholamine and cortisol stress responses in zebrafish.

Both adrenal catecholamines and steroids are known to be involved in the stress response, immune function, blood pressure and energy homeostasis. The response to stress is characterized by the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary system, though the correlation with activation and development is not well understood. We evaluated the stress response of both cortisol and catecholamines during development in zebrafish. Zebrafish at two different stages of development were stressed in one of two different ways and cortisol and catecholamine were measured. Cortisol was measured by enzyme immune assay and catecholamine was measured by ELISA. Our results show that stress responses are delayed until after the synthesis of both cortisol and catecholamines. These observations suggest that the development of HPA axis may be required for the acquisition of the stress response for cortisol and catecholamines.

Current estimate of Down Syndrome population prevalence in the United States.

OBJECTIVE: To calculate a reliable estimate of the population prevalence of Down syndrome in the US. STUDY DESIGN: The annual number of births of infants with Down syndrome were estimated by applying published birth prevalence rates of Down syndrome by maternal age to US data from the Centers for Disease Control and Prevention for the years for which births by maternal age were available (1940-2008). Death certificate data for persons with Down syndrome were available for the years 1968-2007. We estimated the number of people with Down syndrome on January 1, 2008, using a life table approach based on proportions of deaths by age. Monte Carlo sampling was used to create 90% uncertainty intervals (UIs) for our estimates. RESULTS: We estimated the January 1, 2008, population prevalence of Down syndrome as approximately 250700 (90% UI, 185900-321700) based on proportions of deaths by age from the most recent 2 years (2006-2007) of death certificate data. This estimate corresponds to a prevalence of 8.27 people with Down syndrome per 10000 population (90% UI, 6.14-10.62). CONCLUSION: Our estimate of Down syndrome prevalence is roughly 25%-40% lower than estimates based solely on current birth prevalence. The results presented here can be considered a starting point for facilitating policy and services planning for persons with Down syndrome.

Down syndrome and personalized medicine: changing paradigms from genotype to phenotype to treatment.

Personalized Medicine represents a paradigm shift in the conceptual framework of research and clinical care. This shift argues that Down syndrome is a treatable condition, and therefore we must invest in research to improve outcomes. Individuals with Down syndrome have varying levels of increased risk for a number of co-morbidities, including infantile spasms and early onset Alzheimer's disease. We will review research in these associated conditions to show how investigators are attempting to identify biomarkers, including genomic, epigenomic, proteomic and metabolomic "signatures" that will predict who may be at risk to develop a specific co-morbidity prior to onset and will provide novel targets for therapeutic development. This Personalized Medicine approach will permit predictive and preventive approaches for individuals at increased risk for co-morbidities. The support for clinical trials among individuals with Down syndrome is beginning to overcome the "culture of intractability" that has surrounded this disorder.

Acute leukemias in children with Down syndrome.

Children with Down syndrome (DS) often present with hematopoietic abnormalities, and are at increased risk of developing leukemia. Specifically, 3-10% of newborns with DS are diagnosed with transient myeloproliferative disease, and children with DS are 500 times more likely to develop acute megakaryoblastic leukemia (AMKL) and 20 times more likely to develop acute lymphoblastic leukemia (ALL) than typical children. This review examines the characteristics of these leukemias and their development in the unique genetic background of trisomy 21. A discussion is also provided for areas of future research and potential therapeutic development.

Call for change in prenatal counseling for Down syndrome.

The American Journal of Medical Genetics Part A is to be congratulated for taking a leadership role by publishing a number of papers challenging the status quo of prenatal counseling for Down syndrome and of care for children and adults with Down syndrome. Parents want to know about the future abilities and potential of their fetus with Down syndrome, not simply negative medical information that may be outdated. Those providing counseling and those providing medical care could benefit from contact with individuals with Down syndrome outside the medical context. It is imperative that each person with Down syndrome be viewed as a unique individual with particular talents. Medical care providers should work with parents to help the child or adult with Down syndrome reach his/her goals.

Personalized medicine for individuals with Down syndrome.

As the cost of whole genome analysis decreases, we have the opportunity to explore the interactions of various gene changes in an individual that lead to their particular phenotype. This will provide the ability to move from the epidemiologic study of groups, in which, the individuals are treated collectively and homogenously, to personalized medicine, and a model in which the individual is recognized and treated as a distinct entity. We will be applying personalized medicine to individuals with Down syndrome in order to understand and develop biomarkers for increased risk of co-morbidities. Personalized medicine will change the "culture of intractability" of Down syndrome.

Down syndrome: national conference on patient registries, research databases, and biobanks.

A December 2010 meeting, "Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks," was jointly sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, MD, and the Global Down Syndrome Foundation (GDSF)/Linda Crnic Institute for Down Syndrome based in Denver, CO. Approximately 70 attendees and organizers from various advocacy groups, federal agencies (Centers for Disease Control and Prevention, and various NIH Institutes, Centers, and Offices), members of industry, clinicians, and researchers from various academic institutions were greeted by Drs. Yvonne Maddox, Deputy Director of NICHD, and Edward McCabe, Executive Director of the Linda Crnic Institute for Down Syndrome. They charged the participants to focus on the separate issues of contact registries, research databases, and biobanks through both podium presentations and breakout session discussions. Among the breakout groups for each of the major sessions, participants were asked to generate responses to questions posed by the organizers concerning these three research resources as they related to Down syndrome and then to report back to the group at large with a summary of their discussions. This report represents a synthesis of the discussions and suggested approaches formulated by the group as a whole.