Phenotypic complexities of rare heterozygous neurexin-1 deletions

Michael B. Fernando, Yu Fan, Yanchun Zhang, Alex Tokolyi, Aleta N. Murphy, Sarah Kammourh, P. J. Michael Deans, Sadaf Ghorbani, Ryan Onatzevitch, Adriana Pero, Christopher Padilla, Sarah E. Williams, Erin K. Flaherty, Iya A. Prytkova, Lei Cao, David A. Knowles, Gang Fang (), Paul A. Slesinger () and Kristen J. Brennand ()
Additional contact information
Michael B. Fernando: Icahn School of Medicine at Mount Sinai
Yu Fan: Icahn School of Medicine at Mount Sinai
Yanchun Zhang: Icahn School of Medicine at Mount Sinai
Alex Tokolyi: New York Genome Center
Aleta N. Murphy: Icahn School of Medicine at Mount Sinai
Sarah Kammourh: Icahn School of Medicine at Mount Sinai
P. J. Michael Deans: Yale School of Medicine
Sadaf Ghorbani: Yale School of Medicine
Ryan Onatzevitch: Icahn School of Medicine at Mount Sinai
Adriana Pero: Icahn School of Medicine at Mount Sinai
Christopher Padilla: Icahn School of Medicine at Mount Sinai
Sarah E. Williams: Icahn School of Medicine at Mount Sinai
Erin K. Flaherty: Icahn School of Medicine at Mount Sinai
Iya A. Prytkova: Icahn School of Medicine at Mount Sinai
Lei Cao: Icahn School of Medicine at Mount Sinai
David A. Knowles: New York Genome Center
Gang Fang: Icahn School of Medicine at Mount Sinai
Paul A. Slesinger: Icahn School of Medicine at Mount Sinai
Kristen J. Brennand: Icahn School of Medicine at Mount Sinai

Nature, 2025, vol. 642, issue 8068, 710-720

Abstract: Abstract Given the large number of genes significantly associated with risk for neuropsychiatric disorders, a critical unanswered question is the extent to which diverse mutations—sometimes affecting the same gene—will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions in NRXN1, which encodes a presynaptic cell-adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns of NRXN1 alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain and are differentially affected by unique (non-recurrent) deletions1. We contrast the cell-type-specific effect of patient-specific mutations in NRXN1 using human-induced pluripotent stem cells, finding that perturbations in NRXN1 splicing result in divergent cell-type-specific synaptic outcomes. Through distinct loss-of-function (LOF) and gain-of-function (GOF) mechanisms, NRXN1+/− deletions cause decreased synaptic activity in glutamatergic neurons, yet increased synaptic activity in GABAergic neurons. Reciprocal isogenic manipulations causally demonstrate that aberrant splicing drives these changes in synaptic activity. For NRXN1 deletions, and perhaps more broadly, precision medicine will require stratifying patients based on whether their gene mutations act through LOF or GOF mechanisms, to achieve individualized restoration of NRXN1 isoform repertoires by increasing wild-type and/or ablating mutant isoforms. Given the increasing number of mutations predicted to engender both LOF and GOF mechanisms in brain disorders, our findings add nuance to future considerations of precision medicine.

Date: 2025
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DOI: 10.1038/s41586-025-08864-9

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