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Consortium Spotlight: Advancing Discoveries in Neurodevelopmental Disorders

April 14 2022

The Developmental Synaptopathies Consortium (DSC) is a network of experts studying three rare genetic syndromes—tuberous sclerosis complex (TSC), Phelan-McDermid syndrome (PMS), and PTEN hamartoma tumor syndrome (PHTS)—that often cause autism spectrum disorder and intellectual disability. Here, program manager Rajna Filip-Dhima, MS, and principal investigator Mustafa Sahin, MD, PhD, share the history of the consortium, current research, and future plans.


What are the overall goals of the DSC?

The overall goal of the consortium is clinical trial readiness in three related genetic causes of autism spectrum disorder (ASD) and intellectual disability (ID): tuberous sclerosis complex (TSC), Phelan-McDermid syndrome (PMS), and PTEN hamartoma tumor syndrome (PHTS). Specifically, we aim to coordinate clinical research across the three disorders we study.

By leveraging the expertise of the neuropsychology and biomarkers teams we work with, we promote a cohesive, collaborative, and integrated consortium that maximizes the combined efforts of our investigators and resources. We serve as a liaison to the organizations we work with, including patient advocacy groups (PAGs), the National Institutes of Health (NIH), and the Rare Diseases Clinical Research Network (RDCRN), to create core processes that serve and meet the needs of the investigators and trainees. We disseminate results from the research we are conducting to the patient and investigator communities, providing outstanding administrative leadership and support.

How did the DSC team come together, and how did you become a part of the RDCRN?

The DSC team came together in 2013. A small group of investigators—including Mustafa Sahin, MD, PhD; Joseph Buxbaum, PhD; Charis Eng, MD, PhD; Alexander Kolevzon, MD; Darcy Krueger, MD, PhD; and Thomas Frazier, PhD—started holding weekly phone calls to discuss how the comparative biology of the genetic disorders they specialize in will help gain a better understanding of ASD and ID, as well as aid in the future discovery of therapeutic trials.

As the discussions for this grant application continued, the team began formulating research projects and adding more site investigators, therefore forming each study team that shaped into the DSC. That same year, we applied for the RDCRN grant and received the wonderful news of the award the following year in 2014.

Can you tell us more about the rare diseases you study?

TSC is a genetic condition that affects many organs and can cause tumors in the skin, kidney, brain, heart, eyes, lungs, and other organs. The severity of TSC can range from mild (such as skin abnormalities) to severe (such as seizures, intellectual disability, or renal failure), with the most common symptoms being developmental delay, seizures, benign tumors, and skin lesions.

PMS, also known as 22q13.3 deletion syndrome, is caused by a loss of a piece of chromosome 22 near the end of the chromosome at a location designated q13.3 or variants in the SHANK3 gene (which is located in the same region). The symptoms of PMS can vary from person to person, but it is typically characterized by low muscle tone, global developmental delay/intellectual disability, motor skills delay, delayed or absent speech, and ASD.

PHTS refers to a group of conditions caused by an alteration in the PTEN gene. Clinically, it includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and ASD. Patients with PTEN mutations typically develop benign growths in different organs of their body, as well as experience skin lesions, developmental delay, cognitive abnormalities, macrocephaly (enlarged head size), and ASD.

What are your current research projects?

We are currently enrolling into three natural history studies:

ASD and ID Determinants in TSC

The purpose of this study is to learn more about children and young adults who have TSC with ASD, TSC with ID, or TSC with both. Researchers in this study are trying to find earlier signs of autism and ID and gain a better understanding of ASD/ID in individuals with TSC so that effective treatments and interventions for ASD/ID can be found.

Mapping the Genotype, Phenotype, and Natural History of PMS

The purpose of this study is to characterize and define PMS using standardized medical, cognitive, and behavioral measures. Additionally, this study will track how PMS develops and progresses using repeated measurements over time, as well as identify genetic factors which contribute to the many different symptoms that different subjects with PMS experience.

Natural History Study of Individuals with Autism and Germline Heterozygous PTEN Mutations

The purpose of this study is to learn more about the symptoms and characteristics of people with ASD and/or PTEN mutations with the goal of gaining more information about risk management and identifying biomarkers (symptoms or characteristics of a disease at a certain stage) for intervention studies.

How has your research impacted patients?

We work closely with the PAGs and design our studies with their feedback. Since not much is known about the progression of these disorders, the PAGs and patient communities are eager to provide their participation in helping us understand these diseases better. We have also performed one of the first intervention trials in PHTS, opening the possibility of future therapeutics for this syndrome. Finally, we are working closely with the PAGs to increase the participation of individuals from backgrounds traditionally underrepresented in rare disease research.

What new research directions or goals are you pursuing?

For this grant cycle, we are aiming to gain a better understanding of the progression of these disorders into adulthood. Our longitudinal studies are among the first to be done in these populations, therefore producing very rich phenotypic and clinical datasets.

We began by focusing only on children during the first cycle of this grant and have now opened the eligibility criteria to include adults and babies as young as 18 months of age. Additionally, we are focusing on identifying electrophysiological biomarkers of synaptic function and connectivity associated with ASD by having a subset of the enrolled participants undergo electroencephalograms (EEGs).

Additionally, we are focusing on enrolling diverse populations into these studies who are Spanish-speaking and/or from underserved communities, while understanding some of the limitations that these groups and the research community are faced with in conducting such research.

How has being part of the RDCRN impacted the DSC’s work?

We benefit from resources provided by the RDCRN which allow us to conduct research in a more standardized and efficient way. The various tools made available to us help in aiming our focus on the research and improving what we do, rather than focusing on how to do certain things. The collaborative environment of the consortium encourages collective efforts toward goals, such as its focus on diversity, harmonization of methods, and standardization of tools, which are all things that make our research work easier and more impactful.

How do you envision that the diseases you study can ultimately be cured?

What is very exciting about the neurodevelopmental disorders we are studying is that there are many potential approaches now available to introduce therapeutics into the nervous system. We are no longer limited to small molecules, but also have access to anti-sense oligonucleotides and gene-based therapies delivered by viruses such as adeno-associated virus (AAV).

There are still some major obstacles in terms of finding the right dosage, right timing, and efficient delivery of these new therapeutics. However, recent successes in neurological diseases such as spinal muscular atrophy give us hope for the future.


The Developmental Synaptopathies Consortium (DSC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). DSC is funded under grant number U54NS092090 as a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH).

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