Comprehensive phenotypes of patients with SYNGAP1-related disorder reveals high rates of epilepsy and autism.

This study looked at 147 people with changes in the SYNGAP1 gene to understand what symptoms they experience. Everyone had developmental delays or intellectual disability, and most (84%) had epilepsy. Many also had autism traits (68%), behavior challenges (68%), sleep problems (61%), and walking difficulties (47%). The researchers found that where the gene change occurs affects which symptoms people have - some locations cause more language problems while others cause less epilepsy.

This registry-based study analyzed 147 patients with pathogenic SYNGAP1 variants to characterize the comprehensive phenotypic spectrum of SYNGAP1-related disorder. All patients had global developmental delay and/or intellectual disability, with 84% diagnosed with epilepsy. Autism spectrum traits were present in 68% of patients, along with behavioral problems (68%), sleep difficulties (61%), and gait abnormalities (47%). The study identified genotype-phenotype relationships, including better language abilities in patients with variants in exons 1-4 compared to exons 5-19, and less frequent epilepsy in those with variants in the SH3 binding motif.

Behavioral problems were significantly associated with anxiety and sleep disorders but not necessarily with autistic traits.

Findings support comprehensive multidisciplinary care including neurology, developmental pediatrics, and behavioral supports. Early autism screening and intervention warranted given 68% prevalence. Sleep and anxiety management may reduce behavioral problems. Genetic counseling should include discussion of high epilepsy risk and variable language outcomes based on variant location.

Registry-based study with potential selection bias and variable data quality from uploaded medical records. No control group comparison. Sample predominantly pediatric (median age 8 years), limiting adult phenotype understanding. Genotype-phenotype analyses may be underpowered for some comparisons.

To delineate the comprehensive phenotypic spectrum of SYNGAP1-related disorder in a large patient cohort aggregated through a digital registry. We obtained de-identified patient data from an online registry. Data were extracted from uploaded medical records. We reclassified all SYNGAP1 variants using American College of Medical Genetics criteria and included patients with pathogenic/likely pathogenic (P/LP) single nucleotide variants or microdeletions incorporating SYNGAP1.

We analyzed neurodevelopmental phenotypes, including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), behavioral disorders, and gait dysfunction for all patients with respect to variant type and location within the SynGAP1 protein. We identified 147 patients (50% male, median age 8 years) with P/LP SYNGAP1 variants from 151 individuals with data available through the database. One hundred nine were truncating variants and 22 were missense. All patients were diagnosed with global developmental delay (GDD) and/or ID, and 123 patients (84%) were diagnosed with epilepsy.

Of those with epilepsy, 73% of patients had GDD diagnosed before epilepsy was diagnosed. Other prominent features included autistic traits (n = 100, 68%), behavioral problems (n = 100, 68%), sleep problems (n = 90, 61%), anxiety (n = 35, 24%), ataxia or abnormal gait (n = 69, 47%), sensory problems (n = 32, 22%), and feeding difficulties (n = 69, 47%). Behavioral problems were more likely in those patients diagnosed with anxiety (odds ratio [OR] 3.6, p = .014) and sleep problems (OR 2.41, p = .015) but not necessarily those with autistic traits. Patients with variants in exons 1-4 were more likely to have the ability to speak in phrases vs those with variants in exons 5-19, and epilepsy occurred less frequently in patients with variants in the SH3 binding motif.

We demonstrate that the data obtained from a digital registry recapitulate earlier but smaller studies of SYNGAP1-related disorder and add additional genotype-phenotype relationships, validating the use of the digital registry. Access to data through digital registries broadens the possibilities for efficient data collection in rare diseases.