The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions.

Jennifer Cooke,Thomas Bourgeron,Declan Murphy,Antonia San José Cáceres,Eva Loth,Louise Gallagher,Ciara J Molloy,Thomas Dinneen

doi:10.3389/fnins.2022.806990

Abstract

Synaptic gene conditions, i.e., “synaptopathies,” involve disruption to genes expressed at the synapse and account for between 0.5 and 2% of autism cases. They provide a unique entry point to understanding the molecular and biological mechanisms underpinning autism-related phenotypes. Phelan-McDermid Syndrome (PMS, also known as 22q13 deletion syndrome) and NRXN1 deletions (NRXN1ds) are two synaptopathies associated with autism and related neurodevelopmental disorders (NDDs). PMS often incorporates disruption to the SHANK3 gene, implicated in excitatory postsynaptic scaffolding, whereas the NRXN1 gene encodes neurexin-1, a presynaptic cell adhesion protein; both are implicated in trans-synaptic signaling in the brain. Around 70% of individuals with PMS and 43–70% of those with NRXN1ds receive a diagnosis of autism, suggesting that alterations in synaptic development may play a crucial role in explaining the aetiology of autism. However, a substantial amount of heterogeneity exists between conditions. Most individuals with PMS have moderate to profound intellectual disability (ID), while those with NRXN1ds have no ID to severe ID. Speech abnormalities are common to both, although appear more severe in PMS. Very little is currently known about the neurocognitive underpinnings of phenotypic presentations in PMS and NRXN1ds. The Synaptic Gene (SynaG) study adopts a gene-first approach and comprehensively assesses these two syndromic forms of autism. The study compliments preclinical efforts within AIMS-2-TRIALS focused on SHANK3 and NRXN1. The aims of the study are to (1) establish the frequency of autism diagnosis and features in individuals with PMS and NRXN1ds, (2) to compare the clinical profile of PMS, NRXN1ds, and individuals with ‘idiopathic’ autism (iASD), (3) to identify mechanistic biomarkers that may account for autistic features and/or heterogeneity in clinical profiles, and (4) investigate the impact of second or multiple genetic hits on heterogeneity in clinical profiles. In the current paper we describe our methodology for phenotyping the sample and our planned comparisons, with information on the necessary adaptations made during the global COVID-19 pandemic. We also describe the demographics of the data collected thus far, including 25 PMS, 36 NRXN1ds, 33 iASD, and 52 NTD participants, and present an interim analysis of autistic features and adaptive functioning.

Highlights

Autism Spectrum Disorder (ASD)1 is characterized by difficulties in communication and social interaction, as well as the presence of restricted and repetitive behaviors and sensory anomalies (American Psychiatric Association [APA], 2013)
25 PMS, 36 NRXN1 deletions (NRXN1ds), 33 iASD, 30 neurotypical development (NTD)-PMS, and 22 NTD-NRXN participants have been enrolled into the SynaG study so far (N = 146)
Post hoc (Dunn’s) pairwise comparisons with Bonferroni correction confirmed that our current PMS (p < 0.01, p < 0.001), iASD, and NTD-PMS groups are younger on average than the NRXN1ds and NTDNRXN groups respectively, in accordance with the comparison sample matching procedures outlined under Section “Sample.” NTD-PMS participants are younger on average than both PMS and iASD participants

Summary

Introduction

Autism Spectrum Disorder (ASD) is characterized by difficulties in communication and social interaction, as well as the presence of restricted and repetitive behaviors and sensory anomalies (American Psychiatric Association [APA], 2013). A significant amount of clinical heterogeneity is observed in autism, with around 70% of people experiencing other conditions, such as ADHD, anxiety, or epilepsy (Simonoff et al, 2008; Hofvander et al, 2009; Ung et al, 2013; Besag, 2018; Boxhoorn et al, 2018; Lukmanji et al, 2019; Hossain et al, 2020). Autism is a highly heritable condition with strong evidence for the contribution of genetic factors including both inherited and rare de novo mutations (Sebat et al, 2007; Buxbaum, 2009; Sanders et al, 2015; Sandin et al, 2017; Bai et al, 2019; Yoon et al, 2021). Genetic profiles may go some way to explaining the clinical heterogeneity observed in autism and provide key insights into phenotypes linked with specific aetiologies

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