The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions
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-McDermi...
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.806990/full |
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| author | Jennifer Cooke Ciara J. Molloy Antonia San José Cáceres Antonia San José Cáceres Antonia San José Cáceres Thomas Dinneen Thomas Bourgeron Declan Murphy Louise Gallagher Eva Loth |
| author_facet | Jennifer Cooke Ciara J. Molloy Antonia San José Cáceres Antonia San José Cáceres Antonia San José Cáceres Thomas Dinneen Thomas Bourgeron Declan Murphy Louise Gallagher Eva Loth |
| author_sort | Jennifer Cooke |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T04:09:10Z |
| format | Article |
| id | doaj.art-8cfd6d1aed9a44a58e08f864e4a56e4f |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-13T04:09:10Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-8cfd6d1aed9a44a58e08f864e4a56e4f2022-12-22T00:00:07ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-02-011610.3389/fnins.2022.806990806990The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 DeletionsJennifer Cooke0Ciara J. Molloy1Antonia San José Cáceres2Antonia San José Cáceres3Antonia San José Cáceres4Thomas Dinneen5Thomas Bourgeron6Declan Murphy7Louise Gallagher8Eva Loth9Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United KingdomDepartment of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, IrelandForensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United KingdomFundación para la Investigación Biomédica del Hospital General Universitario Gregorio Marañón, Madrid, SpainBiomedical Research Networking Center for Mental Health Network (CIBERSAM), Madrid, SpainDepartment of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, IrelandDepartment of Neuroscience, Institut Pasteur, Paris, FranceForensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United KingdomDepartment of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, IrelandForensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United KingdomSynaptic 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.https://www.frontiersin.org/articles/10.3389/fnins.2022.806990/fullsynaptopathiesautismrare genetic variantsbiomarkerPhelan-McDermid syndromeNRXN1 deletion |
| spellingShingle | Jennifer Cooke Ciara J. Molloy Antonia San José Cáceres Antonia San José Cáceres Antonia San José Cáceres Thomas Dinneen Thomas Bourgeron Declan Murphy Louise Gallagher Eva Loth The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions Frontiers in Neuroscience synaptopathies autism rare genetic variants biomarker Phelan-McDermid syndrome NRXN1 deletion |
| title | The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions |
| title_full | The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions |
| title_fullStr | The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions |
| title_full_unstemmed | The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions |
| title_short | The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions |
| title_sort | synaptic gene study design and methodology to identify neurocognitive markers in phelan mcdermid syndrome and nrxn1 deletions |
| topic | synaptopathies autism rare genetic variants biomarker Phelan-McDermid syndrome NRXN1 deletion |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.806990/full |
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