The following describes the branch’s research programs and program areas.
Cytogenetic abnormalities, which may include chromosomal monosomy or trisomy (such as Down syndrome), mosaicism, or rearrangements, such as deletions or duplications, cause a significant proportion of cognitive impairment and morbidity and mortality, especially among infants and children with intellectual and developmental disabilities (IDDs) or genetic syndromes.
The ability to sequence and analyze whole exomes and whole genomes has provided an unprecedented window into human health and disease. This application of massively parallel, high-throughput next-generation sequencing has also transformed many aspects of research and clinical medicine. In the field of IDDs, genomic approaches are being used for diagnosis when a clear genetic syndrome or genetic cause has not previously been identified; it has the potential to uncover many new genes implicated in human neurodevelopment and neurological function. Other genetic conditions may be caused by mutations that affect epigenetic mechanisms or somatic mutations.
Many branch-supported programs conduct research that falls within this program area, including:
- Eunice Kennedy Shriver IDD Research Centers (EKS IDDRCs)
- Centers for Collaborative Research in Fragile X
- Paul D. Wellstone Muscular Dystrophy Specialized Research Centers (MDSRCs)
Although research on Down syndrome falls into this program area, we provide more detailed descriptions of some these efforts in the Down Syndrome Activities section.
Studies of genetics, genomics, and epigenetics are a core portion of the IDDB portfolio and represent exciting new areas of research for NICHD.
Program Official: Bettina Buhring
IDDB supports studies that, using IDD-relevant animal and cellular models, examine how genomic changes influence brain development and intellectual, social, and affective outcomes. Levels of analysis can span from molecular, genomic, and cellular to systems neuroscience, including large-scale in vivo behavioral electrophysiology and neuroimaging. While molecular studies lay the foundation for understanding cellular brain processes, emergent properties such as working memory, attention, learning, reasoning, inference, and emotion regulation will likely require understanding of how large populations of neurons route and process information within the brain. Of particular interest to IDDB are studies that causally link these levels of analysis, from genomic to systems neuroscience.
Neurobiological findings should be linked closely to behaviors that are relevant in IDD, ranging from cognitive to affective and social tasks. The behavioral tasks should be carefully chosen and interpreted, without applying human diagnoses to animal behavior. Behavioral tasks should test domains of function, such as learning and memory, reasoning, attention, emotion regulation, and social processes, that would enhance quality of life and/or functional skills significantly if improved in individuals with IDD.
IDDB also fosters innovative basic science approaches to treating and preventing IDD, ranging from gene-based therapies to circuit-level interventions that improve neural processing across multiple brain regions. The branch supports early-stage research on potential interventions, whether in animals or humans, as well as studies of biomarkers and outcome measures that can pave the way for clinical trials.
Program Officials: Mollie Minear, Tracy King, Sujata Bardhan, Melissa Parisi
Because biochemical pathways are fundamental to normal body and brain function, changes in those pathways can disrupt not only the pathway itself, but also the processes and functions that rely on the pathway’s products and byproducts.
IDDB funds research on biochemical processes and metabolism as these topics relate to brain functioning, brain injury, and long-term consequences to the brain. The branch’s efforts include research in hypoxia/ischemia, mitochondrial disorders, and many inborn errors of metabolism, including urea cycle disorders, lysosomal storage disorders, errors of amino acid metabolism (e.g., phenylalanine hydroxylase deficiency or phenylketonuria), organic acidemias (e.g., propionic acidemia), and disorders of cholesterol metabolism, among others. IDDB also supports development of therapies and interventions to treat these conditions.
Certain components of the branch-funded Rare Diseases Clinical Research Consortia, such as the Urea Cycle Disorders Consortium, are relevant to this program area. Likewise, some research conducted through EKS IDDRCs, the Centers for Collaborative Research in Fragile X, and MDSRCs, also address topics in this research area.
Program Official: Mollie Minear
Newborn screening research initiatives within NICHD and specifically within IDDB have experienced considerable growth during the past decade. Newborn screening enables identification of infants who are at risk for congenital disorders (often biochemical, hematologic, endocrinologic, and/or genetic) for which early interventions and treatments have the potential to reduce morbidity and mortality.
NICHD helped pioneer newborn screening. Check out this Brief History of Newborn Screening to learn more.
Although routine screening has occurred at the state level since the 1970s, available screening tests have historically varied significantly by state; similarly, few states have evaluated the rationale for or efficacy of the tests systematically. Because these programs screen more than 4 million U.S. infants per year, newborn screening represents the most common form of genetic testing performed in the United States.
The Hunter Kelly Newborn Screening Research Program, established within IDDB in 2009, focuses on developing systematic methods to identify conditions appropriate for newborn screening, developing, and testing innovative interventions and treatments to improve outcomes, educating the provider workforce, developing and implementing appropriate information and communication systems for parents and providers, and sponsoring ongoing programs of research and research training in newborn screening.
One of the resources created to support investigators in the newborn screening community is the Newborn Screening Translational Research Network, a contract awarded to the American College of Medical Genetics and Genomics to provide infrastructure for research to advance diagnostics and treatment of newborn screening disorders and conditions that may be amenable to newborn screening. Some of the resources developed by the network include a virtual repository of states, subjects, and samples of dried bloodspots; support for laboratory testing algorithms and decision matrices; information about new or potential disorders for newborn screening; and development of databases to allow long-term follow-up studies.
Program Official: Alice Kau
ASDs are complex neurodevelopmental disorders characterized by intellectual problems, language problems, and other medical or genetic conditions that relate or contribute to autism, such as seizures or Fragile X syndrome. The most recent ASD prevalence estimates from the Centers for Disease Control and Prevention are available at https://www.cdc.gov/ncbddd/autism/data.html.
During the last 20 years, NICHD has supported a considerable number of research projects related to ASDs. NICHD’s past autism research efforts include the Collaborative Programs of Excellence in Autism (CPEA) Network on the Neurobiology and Genetics of Autism, and the Studies to Advance Autism Research and Treatment (STAART) Network.
In 2007, to maximize coordination and cohesion of NIH-sponsored efforts in autism research, NIH consolidated the CPEA and STAART Networks into the trans-NIH Autism Centers of Excellence (ACE) program. NICHD is one of the five NIH Institutes sponsoring the ACE program, which also receives support from National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Deafness and Other Communication Disorders (NIDCD), and National Institute of Environmental Health Services (NIEHS).
The ACE program includes research centers that foster collaboration between teams of specialists who share the same facility to address a particular research problem in depth. ACE research networks consist of researchers at many facilities throughout the country, all of whom work together on a single research question.
NIH is currently accepting applications for the next funding cycle of the ACE centers and networks through two Requests for Applications (RFAs): RFA-HD-22-008: Autism Centers of Excellence: Centers (P50 Clinical Trial Optional) and RFA-HD-22-007: Autism Centers of Excellence: Networks (R01 Clinical Trial Optional).
Program Officials: Melissa Parisi, Sujata Bardhan, Tracy King, Mollie Minear
Research on Down syndrome has been a central part of the institute’s mission since it was founded. Most of these activities have been and continue to be supported, managed, and coordinated through IDDB.
For example, the branch leads the activities of the Trans-NIH Down Syndrome Working Group, which launched in 2006 to coordinate ongoing research and enhance new efforts on Down syndrome. The following year, the branch developed the first NIH Research Plan on Down Syndrome, with input from outside scientific, family, and advocacy groups, and its follow-up, Down Syndrome Directions: NIH Research Plan on Down Syndrome (PDF 773 KB).
In 2011, NIH and organizations interested in Down syndrome formed the Down Syndrome Consortium to encourage the exchange of information about Down syndrome research, support, and care. Led by IDDB, the Down Syndrome Consortium includes members of the trans-NIH Down Syndrome Working Group and national and international organizations and foundations that focus on Down syndrome and its related health issues, along with self-advocates.
Among the Consortium’s first activities was the creation of DS-Connect®: The Down Syndrome Registry, a confidential online health registry for people with Down syndrome, their families, and healthcare providers and researchers are care for and study the health of people with Down syndrome. NICHD leads the DS-Connect effort through the IDDB.
In June 2018, NIH launched the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project to address critical health and quality-of-life needs for individuals with Down syndrome. INCLUDE studies conditions that affect individuals with Down syndrome and the general population, such as Alzheimer’s disease/dementia, autism, cataracts, celiac disease, congenital heart disease, and diabetes. IDDB leads multiple INCLUDE activities and is leveraging existing Down syndrome research and outreach efforts to augment the power of the INCLUDE project.
IDDB is currently working across NIH on the INCLUDE Down Syndrome Research Plan. A draft of the plan is currently available; the final draft of the plan will be published in early 2022.