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

Abstract

Objective: To delineate the comprehensive phenotypic spectrum of SYNGAP1-related disorder in a large patient cohort aggregated through a digital registry.

Methods: 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.

Results: 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.

Significance: 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.

Keywords: SYNGAP1; developmental and epileptic encephalopathy; epilepsy with eyelid myoclonia; epilepsy with myoclonic–atonic seizures; genetic generalized epilepsy; intellectual disability.

FIGURE 1

Schematic of recurrent pathogenic and likely pathogenic variants in SYNGAP1 in this study. Note that these recurrent variants include amino acid substitutions generating premature stop codons, frameshift variants, an out-of-frame deletion resulting in premature truncations, and intronic variants predicted to result in splice-site alterations. Numbers in parentheses indicate the number of individuals with each variant in the digital registry.

FIGURE 2

Schematic of missense variants in SYNGAP1 in the registry. Note that most SYNGAP1 missense variants affect the PH, C2, and Ras-Gap domains, and no recurrent variants were observed in this study. AA, amino acid residue.

FIGURE 3

Probability of neurodevelopmental conditions by age in SYNGAP1-related disorder. Gray shadow indicates 95% confidence interval. Vertical lines indicate removal of an individual from analysis due to data not being available for an individual beyond age at vertical line. Number at risk in strata below graph indicate number of individuals at the age in the cohort who have not yet been diagnosed with the outcome. (A) Epilepsy. (B) Autism spectrum disorder (ASD). (C) Behavioral problems. (D) Ataxia or abnormal gait.

FIGURE 4

Age at developmental milestone attainment in SYNGAP1-related disorder. Gray shadows indicate 95% confidence interval. Vertical lines indicate removal of an individual from analysis due to data not being available for an individual beyond age at vertical line. (A) Independent walking. (B) Speaking first word. (C) Speaking in phrases.

FIGURE 5

(A) Phenotype of SYNGAP1-rlated disorder associated with SYNGAP1 pathogenic or likely pathogenic single nucleotide variants and microdeletions. *Attention-deficit/hyperactivity disorder (ADHD) is the only phenotypic feature of those listed above that has significant difference between types of variants. No significant difference was observed between types of variants for the seizure types. (B) Seizure types seen in the cohort of individuals with SYNGAP1-related disorder. Note that 100 individuals also had seizures of unspecified classification and, because unclassified, were not included here.