The SYNGAP1 gene, recently recognized for its role in intellectual disability and epilepsy, may also affect the sensory system of patients with a genetic mutation linked to this gene.

That’s the surprising finding of a new study led by scientists at CHU Sainte-Justine and Université de Montréal published in Brain.

"Our novel findings reveal that pathogenic mutations in the SYNGAP1 gene are associated with sensory processing disorders – the misinterpretation of information perceived by the senses – in both preclinical and clinical models," said first author Maria Isabel Carreño-Muñoz, a postdoctoral fellow in UdeM’s Department of Neuroscience.

"This discovery has helped us to identify robust, reproducible and translatable biomarkers in humans that have the potential to guide us in developing new therapies to benefit the patient," she said.

Intellectual disability is the most common cognitive disorder in childhood, affecting one to three percent of the world's population. Among the many genes involved, SYNGAP1 is significant because of its prevalence and the wide range of co-morbidities associated with its mutation, including disturbances of sensory perception. These afflictions significantly interfere with social adaptation and behavioural preferences, and limit a patient’s quality of life.

A cascade of adverse effects

In humans, each healthy cell contains 23 pairs of chromosomes, with each chromosome inherited from one parent. Chromosomes contain genes that are made up of DNA. Genes are also duplicated in our cells and these two copies are called "alleles". The SYNGAP1 gene causes intellectual disability specifically through a mechanism called "haploinsufficiency," in wich one of the two alleles is missing. This leads to a cascade of additional adverse effects resulting in neurodevelopmental disorders.

"This range of afflictions includes intellectual disability, epilepsy, autistic traits and other behavioural changes, in particular language problems, stereotyped behaviour, impulsivity, inattention or aggressiveness," said the study’s co-author, UdeM neurosciences professor Graziella Di Cristo, a researcher at CHU Sainte-Justine and supervisor of Carreño-Muñoz’s work.

"Everyone has their own capacity for 'habituation,'" continued Carreño-Muñoz. "For example, a sensory stimulus, like a noise, may seem intense at first; the brain gradually initiates a process that allows us to tune out the stimulus. But we have found that in SYNGAP1 individuals, there is no adaptation."

By analyzing the brain's response to visual and auditory stimuli in mice through electroencephalographic recordings, the research team identified specific changes in many aspects of sensory processing, including a habituation deficit to auditory stimuli and a much-reduced neuronal response to visual stimuli.

Two processes at play

"We used two processes," said Carreño-Muñoz. "One was the traditional method of studying the evoked sensory response by observing the overall level of the brain’s electrical activity produced as a result of the stimuli. However, the results in mice and humans were inconsistent.

"Simultaneously, we applied a technique called 'neural coupling' that measures the synchronization of slow and fast waves during these same stimulation periods. Each wave is characteristic of a behaviour or of a brain state and indicates that different neuronal populations are at work simultaneously.

"Our analyses have shown that, in the cortex of SYNGAP1 individuals, the work of different neural populations is abnormal and hypersynchronized."

Added co-author Sarah Lippé, an UdeM neuropsychology professor and clinician-researcher at CHU Sainte-Justine: "This second technique provided us with much more consistent results. Our analyses in a cohort of SYNGAP1 patients at CHU Sainte-Justine revealed that most of these changes also occur in children and adolescents, making them good potential biomarkers in humans."

The CHU Sainte-Justine was the first to implicate SYNGAP1 gene as a cause of neurodevelopmental disorder. To date, more than 800 SYNGAP1 patients have been identified worldwide through genetic sequencing, a number that continues to grow as genetic testing increases.

"Knowing that sensory perception is altered in SYNGAP1 gene haploinsufficiency opens the door to new therapeutic pathways to target these abnormalities," said Di Cristo. "In addition, we hypothesize that the sensory system anomalies would influence the seizures observed in SYNGAP1 patients, but we need to continue our research to establish an exact link."