De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Abstract

De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase‐activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi‐gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss‐of‐function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate‐to‐severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide‐based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Genetic and neurodevelopmental spectrum ofSYNGAP1-associated intellectual disability and epilepsy

“…Truncal hypotonia, sometimes in association with facial hypotonia, was the main recurrent feature in our patients, in line with previous series 20 23. Likewise, ataxia, with a broad-based or clumsy gait, was frequent in our patients and recurrently mentioned in others 20 23.…”

“…In total, 47 patients (including two monozygotic twins23) carrying 43 different point mutation or indels limited to the SYNGAP1 gene have been described to date (figure 1 and online supplementary table S3). Three recurrent mutations (c.321_324del, c.427C>T/p.Arg143*, c.1685C>T/p.Pro562Leu) were found in two patients each.…”

“…Recently, seven SYNGAP1 mutations were identified by exome sequencing in a series of 1133 patients, 83% of whom had ID, indicating a frequency of SYNGAP1 mutation of ∼0.74% in patients with ID 25. One patient with a chromosomal translocation interrupting SYNGAP1 26 and five patients with 6p21.3 deletions encompassing SYNGAP1 23 27–30 have also been reported. Thus, to date, SYNGAP1 appears one of the most relevant ID-causing genes, with mutations possibly explaining 0.7 to 1% of ID.…”

Improved Scalability of Neuron-Based Phenotypic Screening Assays for Therapeutic Discovery in Neuropsychiatric Disorders

“…Pathogenic Syngap1 variants cause a genetically defined form of intellectual disability [19] with epilepsy [20], termed MRD5, that accounts for up to 0.5-1% of severe childhood brain disorders [21,22]. This disorder is caused by de novo SYNGAP1 mutations that induce genetic haploinsufficiency [23,24]. Probes that increase Syngap1 expression in neurons would target the root cause of MRD5.…”

Clinical Transcriptome Sequencing Confirms Activation of a Cryptic Splice Site in Suspected SYNGAP1-Related Disorder

“…Brain imaging is typically normal or reveals nonspecific findings. In some, seizure control is achieved with one or more antiepileptic drugs; in others, epilepsy remains pharmacoresistant [Parker et al, 2015;Mignot et al, 2016;Weldon et al, 2018].…”