Autism and rare genetic conditions
Overview of The Synaptic Gene Study (SynaG)
Around 1 in 10 autistic people also have a rare genetic condition that may play a role in their characteristics. The Synaptic Gene Study (SynaG) focused on two such conditions: Phelan-McDermid Syndrome (PMD) and NRXN1 deletion. While each condition is rare, they provide an important opportunity to better understand the biological mechanisms underlying autism. Approximately 70% of individuals with PMD and 30–70% of individuals with NRXN1 deletions are also autistic, although not everyone with these conditions develops autism.
PMD is most commonly caused by a deletion on chromosome 22 (22q13 deletion), which often includes the SHANK3 gene. NRXN1 deletions affect the NRXN1 gene on chromosome 2 (2p16.3 deletion). It is known that rare variations in the SHANK3 and NRXN1 genes affect nerve cells, called neurons, which are the building blocks of the brain. The variations in these genes affect the way that neurons develop and communicate with each other across junctions, called synapses. Changes to the structure and function of neurons could have broad effects on how a person thinks and behaves.
The SynaG Study used a “gene-first” approach to investigate how changes in synaptic genes influence brain development and behaviour. The study included individuals with PMD, NRXN1 deletion, autistic individuals without a known genetic cause (referred to as ‘idiopathic’ autism), and typically developing individuals. Using cognitive testing, questionnaires, eye-tracking, magnetic resonance imaging (MRI), electroencephalography (EEG), and genetic testing the project aimed to identify both shared and distinct features across groups. This multi-method study protocol was designed to ensure rigorous and transparent investigation of neurocognitive, behavioural, and brain-based markers (Cooke & Molloy et al., 2022).
Study Aims
1. Establish the frequency of autism diagnosis and features in individuals with PMS and NRXN1 deletion
2. Compare the clinical profiles of PMD, NRXN1 deletion, and individuals with idiopathic autism
3. Identify mechanistic biomarkers that may account for autistic features and/or heterogeneity in clinical profiles.
4. Investigate the impact of second or multiple genetic hits on heterogeneity in clinical profiles.
Key findings from the SynaG Study
Similarities and differences in social attention in PMD and ‘idiopathic’ autism (Aim 1)
Social attention relates to how much a person focuses on people, faces, or social cues versus objects or non-social stimuli. This aspect of social development is often altered in neurodevelopmental conditions such as autism. Using a semi-naturalistic behavioural measure of social attention, we found that overall, both PMD and idiopathic autism groups paid less attention to social cues compared to typically developing children, however there was substantial variability between individuals (San José Cáceres et al., 2024). Important differences also emerged; while autistic and typically developing individuals showed a preference for social over non-social stimuli, individuals with PMD did not show a clear preference for social over non-social cues. In addition, patterns of attention were linked to developmental level (or mental age) in autistic children, and to autistic traits in PMD. These findings highlight the importance of considering individual differences within both autism and PMD.
Preclinical and clinical research to understand how underlying biological mechanisms relates to behaviour (Aims 2 & 3)
The SynaG study was motivated by growing evidence that PMD and NRXN1 deletions are “synaptopathies”, meaning conditions that affect how synapses function. One theory suggests that disruptions to the balance between excitatory and inhibitory signalling in the brain may contribute to autism-related features.
In a review article, we summarised existing preclinical (cell and animal models) and clinical research evidence of changes in synaptic signalling related to SHANK3 and NRXN1, and how disruptions at synapses may affect brain development, learning, and behaviour (Molloy et al., 2023). We emphasised that while studies using cell and animal models have provided critical insights into brain mechanisms disrupted in PMD and NRXN1 deletions, translating these findings to understand human behaviour remains challenging. We also found limited clinical, behavioural and neuroimaging research in people carrying NRXN1 deletions, emphasising the importance of the SynaG study goal to determine whether brain and neurocognitive measures may identify robust biomarkers.
Alignment between preclinical and clinical research may provide a solution to identification of biomarkers that translate to studies of human, which may guide the development of targeted, personalised supports.
Cognition and brain function in NRXN1 deletions (Aim 3)
While cognitive impacts are observed across many rare neurodevelopmental-related CNVs, our literature review indicated, there is wide heterogeneity within and between these conditions (Molloy et al., 2023). Further, we found limited research directly examining cognition in people with NRXN1 deletions. A deeper understanding of cognitive profiles, including both strengths and challenges, could help identify individual support and educational needs, improve genetic counselling for families, and lead to better clinical outcomes.
We provided the first research evidence that carriers of NRXN1 deletions show distinct cognitive profiles and neural connectivity, significantly advancing our understanding of genotype–phenotype links and laying critical groundwork for biologically informed brain and cognitive markers (Fitzgerald & Molloy et al., 2025). We found weaker connectivity within visual and attention networks, as well as reduced separation between visual and default mode networks. Reduced functional connectivity was also observed in the dorsal anterior cingulate cortex, a brain region involved in attention and decision-making. Together, these findings suggest that altered synaptic functioning may influence both cognition and large-scale brain network organisation in NRXN1 deletion carriers, and suggests a gene-first approach may have potential for identifying biologically informed subgroups.
Explaining individual differences in clinical and behavioural outcomes (Aim 4)
A key aim of the SynaG study was to understand why individuals with the same genetic condition can have very different outcomes. This variability, known as incomplete penetrance, is common in many rare neurodevelopmental-related genetic and CNV conditions.
Our hypothesis is that additional genetic factors may help explain these differences, which may be an effect of an additional rare genetic variant or common variation (Dinneen et al., 2022). We found that polygenic scores, which capture the combined effect of many common genetic variants, were associated with differences in cognitive ability in individuals with other neurodevelopmental-related CNV, known as 15q11.2 deletions and 16p13.11 duplications (Dinneen et al. 2024). This suggests that both rare and common genetic variation contribute to individual differences in outcomes. Next, we will explore this hypothesis in NRXN1 deletion using genomic and behavioural data.
Impact and using research knowledge to develop resources
Overall, the SynaG study has provided new insights into how rare genetic conditions may influence brain function, cognition, and behaviour. By combining genetic, cognitive, and brain imaging approaches, this work is helping to identify biologically meaningful subgroups and better understand the diversity of autism. Ultimately, this research may support the development of more targeted and personalised approaches to intervention in the future.
Along with advancing scientific understanding, the SynaG study team disseminated research updates through family newsletters, family and researcher conferences (e.g., NRXN1 Network), and developed further projects to create research informed resources for families. For example, an accessible short storybook for families impacted by NRXN1 deletions was created with an artist and feedback from families to explain the condition, including strengths and challenges, in a clear and supportive way for families.
If you are a family impacted by NRXN1 deletion and would like a copy of the short storybook you can contact Ciara Molloy at Ciara.molloy@tcd.ie.
The SynaG Study Publications
Cooke, J., C. J. Molloy, A. S. J. Caceres, T. Dinneen, T. Bourgeron, D. Murphy, L. Gallagher and E. Loth (2022). “The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions.” Front Neurosci 16: 806990.
Dinneen, T. J., N. G. F, C. Ormond, E. A. Heron, G. Kirov, L. M. Lopez and L. Gallagher (2024). “Polygenic scores stratify neurodevelopmental copy number variant carrier cognitive outcomes in the UK Biobank.” NPJ Genom Med 9(1): 43.
Dinneen, T. J., F. Ní Ghrálaigh, C. Ormond, E. A. Heron, G. Kirov, L. M. Lopez and L. Gallagher (2024). “Polygenic scores stratify neurodevelopmental copy number variant carrier cognitive outcomes in the UK Biobank.” npj Genomic Medicine 2024 9:1 9(1): 1-9.
Fitzgerald, J., C. J. Molloy, T. Dinneen, N. E. Feerick, M. O’Sullivan, R. O’Conaill, M. Al-Shehhi, R. Reilly, S. A. Lynch, E. A. Heron, C. Kelly, S. Shen and L. Gallagher (2025). “Evidence of neurocognitive and resting state functional connectivity differences in carriers of NRXN1 deletions.” J Neurodev Disord 17(1): 62.
Molloy, C. J., J. Cooke, N. J. F. Gatford, A. Rivera-Olvera, S. Avazzadeh, J. R. Homberg, J. Grandjean, C. Fernandes, S. Shen, E. Loth, D. P. Srivastava and L. Gallagher (2023). “Bridging the translational gap: what can synaptopathies tell us about autism?” Front Mol Neurosci 16: 1191323.
Molloy, C. J., C. Quigley, A. McNicholas, L. Lisanti and L. Gallagher (2023). “A review of the cognitive impact of neurodevelopmental and neuropsychiatric associated copy number variants.” Transl Psychiatry 13(1): 116.
San José Cáceres, A., E. Wilkinson, J. Cooke, V. Baskett, C. Blackmore, D. V. Crawley, A. Durkin, D. Halpern, M. Núñez, P. Siper, D. G. Murphy, J. Foss-Feig, A. Kolevzon and E. Loth (2024). “Investigating social orienting in children with Phelan-McDermid syndrome and ‘idiopathic’ autism.” Journal of Neurodevelopmental Disorders 16(1): 64
Other Resources:
“Ned & Nelly’s NRXN1 Deletion Study”: 2P16.3 (NRXN1) Deletion Resources – Medicine | Trinity College Dublin
Leaders of the SynaG study
Name: Synaptic Gene Project (SynaG)
Lead organisation: Trinity College Dublin, King’s College London
Lead: Prof Louise Gallagher, Dr Eva Loth
Principle Investigators: Dr Eva Loth (Phelan McDermid Syndrome study), Prof Louise Gallagher (NRXN1 study)
Research Centres: King’s College London, Trinity College Dublin
