In addition to cognitive impairments, neurodevelopmental disorders (NDDs) often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with NDDs are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex (SSC) weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina SSC neurons. These results were unexpected given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients.

BackgroundPathologic mutations in SYNGAP1 cause a genetically defined form of intellectual disability (ID) with comorbid epilepsy and autistic features. While only recently discovered, pathogenicity of this gene is a relatively frequent genetic cause of classically undefined developmental delay that progresses to ID with commonly occurring comorbidities.Main bodyA meeting of 150 people was held that included affected individuals and their caregivers, clinicians that treat this and related brain disorders, neuroscientists that study SYNGAP1 biology or the function of related genes, and representatives from government agencies that fund science and approve new medical treatments. The meeting focused on developing a consensus among all stakeholders as to how best to achieve a more fundamental and profound understanding of SYNGAP1 biology and its role in human disease.Short conclusionFrom all of these proceedings, several areas of consensus emerged. The clinicians and geneticists agreed that the prevalence of epilepsy and sensory processing impairments in SYNGAP1-related brain disorders approached 100%. The neurobiologists agreed that more basic research is needed to better understand the molecular and cellular functions of the Syngap1 gene, which will lead to targets for therapeutic intervention. Finally, everyone agreed that there is a pressing need to form a robust patient registry as an initial step toward a prospective natural history study of patients with pathogenic SYNGAP1 variants.

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Objectives: SYNGAP1-NSID is thought to result from limited functional levels of SynGAP protein, a protein critical in proper brain development and function. Predominantly affecting children, SYNGAP1 mutations lead to developmental delay, intellectual disability, and additional symptoms that are common with other causes. As such, confirmation of SYNGAP-related NSID is through genetic testing. To improve awareness and understanding of SYNGAP-related NSID and better inform treatment development, the Bridge the Gap Education and Research Foundation, in partnership with the National Organization for Rare Disorders and support from the US Food and Drug Administration, launched the SYNGAP1 (MRD5) patient registry in 2017. Here, we describe patient demographics, diagnoses, and quality of life in registry patients. Methods: The registry contains 13 surveys covering diagnostics, disease, treatment, care management, and quality of life. As of December 2018, 105 patients have provided data for 717 survey submissions. Results: Registry participants are mostly white (89%, 93/105) and female (54%, 57/105) and reside in 21 countries with 54% (57/105) US-based. All respondents (78/78) indicated genetic testing in the SYNGAP diagnosis process. Most patients were also diagnosed with epilepsy (83%, 48/58) and/or autism spectrum disorder (55%, 32/58). Additional reported diagnoses or conditions included impaired or delayed gross motor skills (98%, 55/56), orthopedic problems (56%, 31/55), sensory disorders (34%, 20/59), skin disorders (26%, 14/54), respiratory issues (7%, 4/55), and/or cardiovascular issues (2%, 1/55). Over half of respondents (54%, 28/52) indicated that their health problems affected every day functioning; 62% (31/50) indicated that health issues limited the ability to perform activities s/he enjoys most. Conclusions: Patients in the registry have significant disease burden and impacted quality of life. Data collection through the SYNGAP1 (MRD5) patient registry continues with the intent of raising awareness of the disease and enabling the development of treatments.