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Background <p><i>NRXN1</i> deletion (<i>NRXN1</i> del) is a rare copy number variant associated with several neurodevelopmental, neuropsychiatric, and cognitive outcomes. The <i>NRXN1</i> gene encodes for a pre-synaptic cell adhesion molecule that is important for synapse formation, regulation and neurotransmission. We used a gene-first approach to investigate neurocognitive and brain phenotypes in <i>NRXN1</i> d<i>e</i>l carriers.</p> Methods <p>Forty-two participants (21 <i>NRXN1</i> del carriers and 21 neurotypical age and sex-matched comparisons) completed IQ assessments, and a neurocognitive battery, including, executive function, attention, and social cognition tasks. Magnetic resonance imaging (MRI) data, including T1-weighted anatomical scans, resting state functional MRI and diffusion tensor imaging, were acquired in 36 participants (17 <i>NRXN1</i> del carriers and 19 comparisons).</p> Results <p><i>NRXN1</i> del carriers had lower mean IQ and poorer spatial working memory performance compared to comparisons (<i>p</i> ≤ 0.05). Neuroimaging results revealed group differences in visual and ventral attention resting state networks (<i>p</i> &lt; 0.05). Network-based statistical analysis showed a significant effect of group status for 28/115 connections, with poorer segregation between visual and default networks in <i>NRXN1</i> del carriers relative to comparisons. No differences in brain structural volume or cortical thickness, or diffusion measures of white matter structural architecture were observed between groups.</p> Conclusions <p>This exploratory study provides evidence for neurocognitive impacts and brain functional differences related to underlying synaptic mechanisms. Brain functional differences in <i>NRXN1</i> del carriers may support altered excitation/inhibition dynamics within the brain. Gene-first approaches may establish brain-based translational markers to identify neurobiologically informed subgroups within neurodevelopmental and neuropsychiatric conditions, and ultimately transdiagnostic therapeutic strategies.</p>

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Evidence of neurocognitive and resting state functional connectivity differences in carriers of NRXN1 deletions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月15日

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  • Jacqueline Fitzgerald,
  • Ciara J. Molloy,
  • Thomas Dinneen,
  • Niamh E. Feerick,
  • Matthew O’Sullivan,
  • Richard O’Conaill,
  • Maryam Al-Shehhi,
  • Richard Reilly,
  • Sally Ann Lynch,
  • Eleisa A. Heron,
  • Clare Kelly,
  • Sanbing Shen,
  • Louise Gallagher

摘要

Background

NRXN1 deletion (NRXN1 del) is a rare copy number variant associated with several neurodevelopmental, neuropsychiatric, and cognitive outcomes. The NRXN1 gene encodes for a pre-synaptic cell adhesion molecule that is important for synapse formation, regulation and neurotransmission. We used a gene-first approach to investigate neurocognitive and brain phenotypes in NRXN1 del carriers.

Methods

Forty-two participants (21 NRXN1 del carriers and 21 neurotypical age and sex-matched comparisons) completed IQ assessments, and a neurocognitive battery, including, executive function, attention, and social cognition tasks. Magnetic resonance imaging (MRI) data, including T1-weighted anatomical scans, resting state functional MRI and diffusion tensor imaging, were acquired in 36 participants (17 NRXN1 del carriers and 19 comparisons).

Results

NRXN1 del carriers had lower mean IQ and poorer spatial working memory performance compared to comparisons (p ≤ 0.05). Neuroimaging results revealed group differences in visual and ventral attention resting state networks (p < 0.05). Network-based statistical analysis showed a significant effect of group status for 28/115 connections, with poorer segregation between visual and default networks in NRXN1 del carriers relative to comparisons. No differences in brain structural volume or cortical thickness, or diffusion measures of white matter structural architecture were observed between groups.

Conclusions

This exploratory study provides evidence for neurocognitive impacts and brain functional differences related to underlying synaptic mechanisms. Brain functional differences in NRXN1 del carriers may support altered excitation/inhibition dynamics within the brain. Gene-first approaches may establish brain-based translational markers to identify neurobiologically informed subgroups within neurodevelopmental and neuropsychiatric conditions, and ultimately transdiagnostic therapeutic strategies.