Omar Shennib
Olivia Raines1
Megan E. Williams- 1Department of Neurobiology, School of Medicine, University of Utah, Salt Lake City, UT, United States
- 2Division of Pediatric Neurology, Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, UT, United States
The synaptic adhesion molecule KIRREL3 regulates synapse development in mice and is implicated in human neurological disorders, including autism spectrum disorder, intellectual disability, and Jacobsen syndrome (chromosome 11q deletion syndrome). However, its status as a definitive human disease gene remains unresolved, likely due to the rarity of KIRREL3-related disorders and significant gaps in understanding its molecular mechanisms. Current knowledge is further fragmented across disparate clinical and basic research reports, often buried in supplemental data. This review synthesizes existing evidence to enable clinicians and scientists to better evaluate KIRREL3 variants as potentially disease causing. We review its conserved role in mediating neuron-to-neuron interactions during axon targeting and synapse formation in mice and how disruptions to these interactions could contribute to neurological pathology in humans. We also discuss how disease-associated variants alter KIRREL3 function. Our analysis underscores the need for integrated studies spanning basic and clinical investigation to validate KIRREL3’s disease association and advance future interventions for KIRREL3-related disorders.
Introduction
KIRREL3 is a member of the small IRM (Irregular cell recognition module) gene family and the only one repeatedly linked to neurological disorders (1–5). Like all IRM proteins, KIRREL3 is a single-pass transmembrane protein (1, 6). IRM proteins are best characterized in non-neural tissues, where they play critical roles in kidney slit diaphragm formation and muscle cell fusion (6–9). These proteins also contribute to neurodevelopmental processes in model organisms, including Drosophila eye formation and C. elegans synaptic connectivity (6, 7, 10–29). Because this important foundational work on invertebrate IRM proteins was reviewed elsewhere (30) and our goal is to translate Kirrel3 knowledge to human neurological diseases, we focus this review on Kirrel3 in brain function and dysfunction of mammals from mice to humans.
Over the past two decades, human genetic studies suggested associations between KIRREL3 (OMIM: 607761) and brain conditions such as autism spectrum disorder, intellectual disability, Jacobsen syndrome, and developmental delay (4, 31–37). However, the role of KIRREL3 as a disease-associated gene remains unresolved in the clinic even though there is supportive evidence of its variant pathogenicity in the scientific literature. Many different types of genetic variants in the KIRREL3 gene, including missense mutations, truncating variants, splice-site alterations, and copy number variants, are reported in the public databases gnomAD, UCSC, VariCarta, and ClinVar (38–41). While some of these variants are classified as pathogenic or likely pathogenic, many others remain classified as variants of uncertain significance (VUS) due to insufficient evidence (41). This uncertainty stems from several factors, including small sample sizes in initial studies, limited functional validation, lack of inheritance information, and inconsistent phenotypic presentations among individuals with KIRREL3 variants. Furthermore, the lack of large-scale, systematic analyses on KIRREL3-related disorders contributes to the unresolved role of KIRREL3 in disease. This leaves clinicians and researchers without clear guidelines for interpretation.
The goal of this work is to provide a side-by-side analysis of what is currently known about KIRREL3 protein function in the mammalian brain, as well as what is known about Kirrel3 gene variants and their associations with neurological diseases. Furthermore, recent analyses also found increases KIRREL3 gene expression to glioma cancer (32, 33). Misexpression of cell adhesion molecules is common in metastatic cancers, however, we will focus on neurological disorders in this review (42). This review will contribute to the understanding of KIRREL3 and serve as a model for resolving gene-disease associations surrounding other genes with similarly unclear disease associations.
KIRREL3 gene and isoforms expression
The human KIRREL3 gene (Kin of IRRE-like 3), also previously known as NEPH2 (43), is located on chromosome 11q24.2 (hg38 chr11:126,423,358-127,000,770), covering 577.413 Kb, with 21 exons (Figure 1A) (39, 44, 45). Its longest and most abundant transcript encodes a single-pass transmembrane protein that is 778 amino acids long with five extracellular immunoglobulin domains and an intracellular region ending in a PDZ binding domain (Figure 1B) (44, 46, 47). Targeted long-read mRNA sequencing revealed the full exon structure and alternative splicing pattern of Kirrel3 in the mouse brain (45). In mice, 19 alternatively spliced isoforms were identified including those with different intracellular domains and secreted forms. The study also analyzed publicly available long-read sequencing data from human brain tissue and identified 11 isoforms in the human brain (45). Although, this number is likely an underestimate because Kirrel3 transcripts are rare and a targeted approach was not used, the patterns were similar to mice in that human KIRREL3 isoforms also had different intracellular domains and secreted forms (45). Interestingly, cross-species comparisons of Kirrel3 transcripts revealed that humans and great apes uniquely possess an additional exon encoding a distinct 30 amino acid insertion in the intracellular domain, suggesting evolutionary specialization (45). However, future work is needed to directly test if different KIRREL3 isoforms, including the hominid-specific exon, have distinct functions in the brain.
Figure 1. Human KIRREL3 gene and protein structures. (A) Genetic map of chromosome 11. Red box covers the KIRREL3 gene (577.413 Kb) on the q arm of chromosome 11. KIRREL3 schematic gene structure shows 21 exons (boxes) and introns (lines). Exon 7, 17, and 19 are reported in unique isoforms and have 5′ extensions and 3′ extensions, indicated by dotted lines. Intron 2–3 is cut short (dashes) to fit in the scaled illustration. (B) KIRREL3 protein structure and protein transhomophilic interaction. Binding structural assay shows the protein binding structure is through the IgD1 via hydrogen bonding at Q128 amino acid position. IgD, immunoglobulin domain; TMD, transmembrane domain; BD, binding domain; PM, plasma membrane.
The KIRREL3 mRNA is expressed in multiple tissues, including the kidney, skeletal muscle, and brain (16, 47, 48). To refine its expression profile using recent datasets, we analyzed RNA-seq and single-nucleus RNA sequencing available on GTEx, Human Protein Atlas, BioGPS, and Allen Brain Atlas (46, 49–51). We found that both human and mouse Kirrel3 mRNA have the highest expression in the brain with enrichment in the cerebral cortex, thalamus, cerebellum, amygdala, hippocampus, and olfactory bulb (Figures 2A,C). Within the brain, Kirrel3 transcription is enriched in three major cell populations: excitatory neurons (amygdala and hippocampal dentate gyrus (DG)), inhibitory neurons (LAMP5-LHX6, Chandelier, and MGE-derived interneurons), and oligodendrocytes (Figures 2B,D). The conserved expression pattern of Kirrel3 in both human and mouse brain cell types, and the high conservation in the gene (94.7%) and protein (98%) sequences, supports the use of mouse models to elucidate its cellular function (52–55).
Figure 2. KIRREL3 expression in human and mouse. (A) RNA sequencing from adult human tissues show KIRREL3 mRNA expression levels higher in brain regions (yellow) than anywhere else. (B) Single nuclei sequencing from human brain shows that KIRREL3 copies are enriched in excitatory and inhibitory neurons, as well as gliodendrocytes. Y-axis shows transcript expression in normalized transcript per million (nTPM). Human transcript expression levels are based on transcriptomics data from two sources: HPA and GTEX. (C) Mouse Kirrel3 mRNA expression is similar to human with high expression in brain regions (yellow). (D) Scatter blot of mouse Kirrel3 transcript expression shows expression in specific cell types throughout the brain. Mouse transcriptomics data are from two sources: BioGFP and Allen Brain Atlas.
KIRREL3 behavioral studies in mouse
Several mouse models were developed to investigate Kirrel3’s role in neurological disorders, including a global knockout, a conditional knockout, and a point mutant knock-in mouse. Kirrel3 knockout mice were used to investigate behavioral phenotypes relevant to neurological disorders and compared to wildtype controls (56–59). Kirrel3 knockout mice exhibit subtle deficits in social recognition and novel object memory, which may be consistent with core features of autism spectrum disorder and intellectual disability in humans (56, 58). Moreover, a recent study revealed that selective activation of Kirrel3-expressing GABAergic neurons in the hippocampus impairs contextual memory discrimination, directly linking Kirrel3-expressing GABA neurons to cognitive processes (59).
Beyond memory functions, Kirrel3 knockout mice show distinct behavioral alterations across multiple neural systems. While basic olfactory function remains intact, knockout mice show reduced male–male aggression (56, 57, 60). Motor assessments yield complex findings, with knockout mice displaying both hyperactivity in open field tests and enhanced coordination on rotarod tasks (56–58, 61). Auditory system evaluation reveals a selective deficit in processing high-intensity sounds (110 dB), while baseline hearing remains unaffected (57). Though molecular mechanisms were investigated in hippocampal and olfactory circuits (See Molecular Mechanisms Section), significant gaps remain in understanding Kirrel3’s precise function in other brain regions. The lack of mechanistic studies in cerebellar and auditory circuits limits our interpretation of the observed behavioral phenotypes. Collectively, Kirrel3 knockout behavioral studies indicate that Kirrel3 subtly influences distinct brain functions in mice, including cognition, olfaction, motor control, and auditory processing. These functions are clinically relevant, as they are commonly disrupted in autism and intellectual disability (62–64). However, a caveat of mouse behavioral studies is that they were done in adult mice and genetic compensation can occur over time. More behavioral assays in juvenile mice are needed to directly assess the developing brain and ameliorate this caveat. Future research using conditional knockout models would clarify Kirrel3’s region-specific effects on mouse brain function. Additionally, although automated tracking methods are propelling the complexity of mouse behavioral research, mice inherently lack the subtle and complex behaviors of humans and direct translation from mouse to human should be interpreted with caution.
Molecular mechanisms of KIRREL3 in mouse
In general, Kirrel3 knockout mice exhibit normal brain and body size throughout development compared to wildtype controls (56–58). Macroscopic-level findings show that Kirrel3 manipulation does not alter gross neuroanatomy but instead affects ultrastructures (52, 56–58, 60, 65, 66). This is similar to autism where there is no clear or consistent pathology at a macroscopic structural level, but it is largely theorized that deficits are at a synaptic and circuit level (63, 67). Thus, we next review mechanistic studies of Kirrel3 in the mammalian brain.
Kirrel3 promotes hippocampal synapse formation
Kirrel3 is expressed selectively in two hippocampal cell populations: excitatory dentate gyrus (DG) neurons and a subset of inhibitory GABAergic neurons (47, 52, 58). Kirrel3 is important for the formation of specialized excitatory synapses onto GABAergic neurons in mice called mossy fiber filopodia synapses (Figures 3A,B) (52, 66). Kirrel3 knockout mice have a significant reduction in the formation of mossy fiber filopodia synapses (66). Because these synapses normally excite GABAergic neurons that, in turn, inhibit CA3 neurons, Kirrel3 knockout mice lack this inhibition and have a corresponding increase in CA3 neuron activity (Figure 3C) (52). Thus, a reduction in excitatory synapses actually increases net brain activity (because they specifically form on inhibitory neurons) and highlights why understanding the precise synapses regulated by neurodevelopmental risk genes is important for developing effective treatment strategies. Unlike disorders involving general excitatory synapse loss, where therapies might aim to boost neuronal activity, KIRREL3-related dysfunction may instead require interventions that decrease neuronal activity.
Figure 3. Kirrel3 functional studies in rodents. (A) A Hippocampal diagram and its relevant regions (DG, CA3 and GABA neurons). (B) Structure of mossy fiber botouns (MFB) and filopodia-GABA synapses in the CA3 region. In the Kirrel3 KO mouse, these synapses are reduced significantly. (C) CA3 neurons have higher excitation/inhibition ratio (E/I) in knockout mice. This is most likely due to the loss of feed-forward inhibition from the DG filopodia-GABA synapse reduction. (D) An olfactory system diagram shows vomeronasal sensory neurons (VSN) projecting axons to form synaptic Kirrel3 homogeneous glomeruli in the accessory olfactory bulb (AOB). (E) Kirrel3 KO and point mutant (Q128A) mice show overall a reduction in glomeruli number compared to wild-type (WT) mouse. (F) In vitro hippocampal culture, over expressing Kirrel3 (K3) patient variants shows similar synapse number to the no overexpression condition in the WT. Only over-expression of Kirrel3 wild-type copy increases the synapse number. This indicates that the Kirrel3 patient variants alter Kirrel3’s synaptic function.
A subsequent study did not directly study KIRREL3 protein function but instead studied the role of the GABA neurons that express Kirrel3 in learning, memory, and circuit activity (59). When these Kirrel3-expressing GABA neurons were activated with chemogenetics, they impaired memory and powerfully suppressed CA3 activity (59), confirming their capacity for circuit inhibition. However, it remains untested whether such activation could rescue the hyperactivity phenotype in knockout mice, a crucial next step for therapeutic development. These results are particularly significant given the established role of GABAergic dysfunction in autism spectrum disorders (68). Importantly, Kirrel3’s expression pattern extends far beyond the hippocampus, and is expressed by specific cell types in many brain regions (Figure 2) (46, 49, 51). Comparative studies across brain regions are needed to test whether Kirrel3’s hippocampal mechanisms generalize to other areas.
Kirrel3 axon coalescence role in the olfactory system
Within the olfactory system, Kirrel3 is expressed in discrete subsets of vomeronasal sensory neurons that converge to form homogeneous glomeruli in the accessory olfactory bulb (Figure 3D) (48, 60, 69, 70). This restricted expression implicates Kirrel3 in helping to establish part of the glomerular map essential for odor and pheromonal processing. Kirrel3 knockout mice display defects in posterior accessory olfactory glomeruli, which appear disorganized and significantly reduced in number compared to wildtype controls (Figure 3E) (48, 60). KIRREL3 is known to mediate synapse formation and cell adhesion through homophilic binding in trans where the KIRREL3 extracellular domain from one cell binds the KIRREL3 extracellular domain on another cell synapses (2, 6, 48, 52, 65, 71, 72). This was shown to occur in vivo through study of a p.Q128A point mutant that breaks the KIRREL3 homophilic trans-cellular binding (71). The mutant mouse phenocopied the glomeruli disruption in knockout mice and microscopic investigation showed that these glomeruli are innervated and heterogeneous (Figure 3E) (71). This indicates that KIRREL3-KIRREL3 trans-cellular binding is necessary for its function in the mouse brain. Olfactory deficits in KIRREL3-related disorders remain understudied, and this wiring mechanism might have broad relevance. The accessory olfactory bulb shares developmental pathways with social brain circuits, and disrupted pheromone processing could contribute to the social behavior impairments seen in patients.
KIRREL3 variants in human neurological disorders
KIRREL3-related disorders have broad phenotypic spectrum and variable symptom severity. Affected individuals present with neurodevelopmental conditions, including autism, intellectual disability, developmental delay, ADHD, or bipolar disorder, often accompanied by dysmorphic facial features, e.g., coarse facies, large ears, and flat nasal bridge (Table 1). Moreover, symptom severity ranges from mild to profound. We explore specific variants and severity correlations in a later section (SNV in clinical cases and Table 2). The link between KIRREL3 and neurological disorders was first discovered through two foundational studies. Grossfeld et al. (73) first identified deletions encompassing KIRREL3 in patients with 11q terminal deletion syndrome. Subsequently, Bhalla et al. (31) made two key discoveries. First, they identified deletion variants in KIRREL3, including a balanced translocation. This chromosomal translocation disrupted both KIRREL3 and CDH15 in a severely affected female patient with an IQ of 16. Second, they reported the first pathogenic single nucleotide variants in KIRREL3. These included three missense mutations, p.R40W, p.R336Q, p.V731F, found in unrelated intellectual disability patients (31, 74). These three variants showed rare allele frequencies (0.0000016–0.000075) suggesting negative selection, and subsequent functional studies confirmed their impairment of synapse formation in vitro (2).
Table 1. Manual curation of well-reported exonic variants.
Table 2. KIRREL3 variants reported with detailed clinical manifestation.
Testing the function of human variants in rodent neurons
KIRREL3 missense variants identified in patients with autism and intellectual disability were functionally tested in a series of experiments using cultured cells and mouse neurons (2). Exogenous expression of wildtype Kirrel3 traffics to the cell membrane, accumulates at synapses, causes cells to adhere to one another, and induces extra synapses in cultured mouse hippocampal excitatory neurons (2). Six variants were tested and trafficked correctly (R40W, R161H, R205Q, R336Q, M673I, and V731F); however, five out of the six variants, excluding M673I, had a reduced ability to induce synapses in cultured hippocampal neurons (Figure 3F) (2). Two variants that were not synaptogenic, p.R205Q and p.V731F, were unable to mediate trans-cellular adhesion, explaining their inability to mediate synapse formation (2). However, p.R40W, p.R161H and p.R336Q variants were not synaptogenic but could mediate cell adhesion normally (2). Together, this indicates that KIRREL3 trans-cellular binding is necessary but not sufficient for its synaptic function. This provides strong support that KIRREL3 is more than just synaptic glue and is also an active molecule in synapse formation. To our knowledge, this is the only study to date to investigate the function of KIRREL3 missense variants found in patients with neurodevelopmental disorders. The fact that most disease-associated variants (5/6) have a clear functional deficit in cell and neuron culture assays strongly suggests that they may contribute to pathogenicity in humans.
SNVs in clinical cases
To gain a better picture of KIRREL3 SNV types from a clinical database, we analyzed 116 clinically validated KIRREL3 variants from ClinVar (41). Human KIRREL3 gene and transcript (NM_032531.4) references are annotated by the NCBI Homo sapiens Annotation Release 109.20200815; however, for the newly discovered exons, we used the most recent published data (45). For allele and variant frequencies, we used gnomAD Joint Variant Frequencies 4.0 v2 (74). We calculated CADD score, if not reported already, for variants in Table 1 using https://cadd.gs.washington.edu/snv.
This analysis reveals two main points. First, variants are distributed across the entire protein (Figures 4A,B), with no obvious clustering toward specific domains. Second, most variants (56%) remain classified as variants of uncertain significance (VUS), with only 2% currently designated as pathogenic on ClinVar. Even functionally tested variants like p.R40W and p.V731F remain classified as VUS, despite evidence that they impair synapse formation in mice (2). This conservative approach suggests current guidelines may underestimate KIRREL3’s clinical importance.
Figure 4. KIRREL3 clinical variants. (A) KIRREL3 protein domains as predicted by SMART and UniProtKB/TrEMBL. Numbers in the bottom are amino acid (aa) number order. Domains are grey shaded to match their corresponding exons in (B). Well-reported variants with detailed clinical manifestations are indicated on the protein domains, see Table 2. Variants with 1 or 2 occurrences are blue, variants with ≥3 occurrence are red. (B) Exons (boxes) are aligned with clinical variants reported on ClinVar. (C) Statistical counts on clinical variants types reported in ClinVar and DECIPHER. (D) Genetic map of KIRREL3 and Kirrel3-IncRNA. IncRNA’s associated mutation was reported in an ASD patient as a potential regulator of the gene. See Methods for details. IgD, immunoglobulin domain; TM, transmembrane; BD, binding domain; VUS, variant of uncertain significance.
We also searched for genetic evidence to establish KIRREL3 as a risk factor for neurological disorders in large-scale studies on autism spectrum disorder and intellectual disability (FDR < 0.1) (2, 3, 5, 31, 75–84). From these studies, we curated 55 exonic SNVs that are well-phenotyped, and the connections are supported by computational predictions showing that many exonic missense variants have high pathogenicity scores (CADD ≥30), indicating strong likelihood of deleterious effects (Table 1) (85). Furthermore, we found that there is a predominance of de novo mutations, with equal maternal and paternal inheritance (75, 76, 80, 81, 86). Interestingly, the extracellular region has three recurrent pathogenic variants, each observed in ≥3 unrelated cases and associated with severe phenotypes, p.R161H, p.R336Q/W, p.A393T/V (Figure 4A in red, Table 2). Table 2 highlights the variants with reported detailed clinical manifestations. Interestingly, both extracellular variants, p.R161H and p.R336Q, disrupt synapse induction in mice (2). The 19 intracellular variants remain poorly characterized beyond the PDZ-binding domain’s putative synaptic scaffolding role (2, 10, 83). The recurrence of pathogenic extracellular variants exhibiting similar severe phenotypes suggests their clinical significance, warranting prioritization in genetic testing. Intracellular variants remain less understood but may contribute to variable expressivity. Future work should address the intracellular domain’s unexplored contributions to KIRREL3-related pathogenesis through structural biology and proteomic approaches. The combination of domain-wide variant distribution, functional evidence, and genetic associations supports KIRREL3 as a clinically significant risk gene in neurological disorders. Improved variant interpretation methods are needed to fully capture the variants’ pathogenic potential.
CNVs in clinical cases
KIRREL3 deletions are a consistent feature of Jacobsen syndrome (chromosome 11q deletion syndrome), which typically results from large (7–20 Mb) terminal deletions at 11q23.3-qter that encompass KIRREL3 (11q24.2) (34, 36, 87). Jacobsen syndrome is a rare genetic disorder characterized by developmental delays, craniofacial dysmorphisms, and variable congenital anomalies. The syndrome’s characteristic intellectual disability appears specifically linked to loss of KIRREL3 gene. This is because two unusual cases with microdeletions (∼700 kb) sparing KIRREL3 presented without intellectual disability (88). This genotype–phenotype correlation strongly suggests KIRREL3 loss is the key contributor to cognitive impairment in Jacobsen syndrome.
We also analyzed other publicly available CNVs in ClinVar and DECIPHER in the same way we analyzed the SNVs in the previous section. KIRREL3 CNVs show significantly high pathogenicity rates, with nearly equal proportions of duplications and deletions (gain and loss) (Figure 4C). Furthermore, the gene’s exceptionally high probability of loss-of-function intolerance (pLI = 0.98), suggests haploinsufficiency as a key disease mechanism in humans (74–76, 80). However, critical gaps remain in correlating these genetic findings with detailed clinical outcomes, as most databases lack comprehensive phenotypic information.
Beyond CNVs that disrupt KIRREL3’s protein-coding sequence, regulatory mechanisms may also contribute to KIRREL3-related neurological disorders. A study of chromosomal abnormalities in genetically undiagnosed neurological cases identified a patient with ADHD and spatial coordination deficits carrying de novo balanced breakpoints at 11q24.2 (89, 90). While no pathogenic coding variants were detected, the breakpoints disrupted ENSG00000255087, a long non-coding RNA (lncRNA) located upstream of KIRREL3 (Figure 4D). Subsequent analysis demonstrated co-occurring KIRREL3 mRNA downregulation in this patient. This suggests that either the lncRNA regulates KIRREL3 gene expression or this region contains an enhancer regulatory element for KIRREL3 gene. These findings highlight the importance of investigating nearby regulatory element variants where non-coding disruptions can phenocopy coding mutations through transcriptional dysregulation.
Future perspectives
Moving forward, research on KIRREL3 should address several critical gaps to fully understand its role in neural circuit development and neurological disorders. While studies revealed essential Kirrel3 functions in hippocampal and olfactory systems, conditional knockout approaches targeting specific neuronal populations will be necessary to dissect its roles in cortical, cerebellar, and other neural circuits. The existence of multiple Kirrel3 isoforms, particularly the distinct secreted and transmembrane forms, presents another crucial area for exploration. Detailed characterization of isoform-specific localization, binding partners, and functional differences could explain the phenotypic variability observed in patients and provide mechanistic insights into how different mutations lead to diverse clinical outcomes.
There are currently no published studies on human iPSC-derived neurons from patients with KIRREL3 mutations. However, human cellular models will be essential for translating findings from animal studies to clinical applications. Patient-derived iPSC neurons with defined KIRREL3 variants offer a powerful platform to validate mechanisms observed in mice while capturing human-specific aspects of neural development. On the clinical front, establishing standardized phenotyping and reporting protocols across clinic centers will be critical for capturing the full spectrum of KIRREL3-related manifestations and correlating them with specific genetic changes.
These future perspectives require collaboration between neurobiologists studying synaptic development, geneticists characterizing variants, and clinicians caring for affected individuals. In conclusion, KIRREL3 emerges as a model for understanding how synaptic adhesion molecules contribute to neurological disorders. Its complex isoform regulation, region-specific circuit functions, and diverse mutational mechanisms illustrate the intricate relationship between molecular neurobiology and clinical presentation.
Author contributions
OS: Formal analysis, Visualization, Writing – original draft, Methodology, Validation, Project administration, Data curation, Investigation, Supervision, Software, Conceptualization, Writing – review & editing. OR: Conceptualization, Writing – review & editing, Investigation. ASK: Writing – review & editing, Validation. MEW: Supervision, Conceptualization, Validation, Project administration, Writing – review & editing, Investigation, Funding acquisition, Writing – original draft, Visualization, Resources.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the R01 MH125943 (MEW) R01 MH134515 (MEW), and Graduate Research Fellowship from University of Utah (OS), and the Pediatric Epilepsy Research Foundation (ASK).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: gene disease association, genotype–phenotype correlation, clinical variant, neurodevelopmental disorders, autism, intellectual disability, cell adhesion molecule, Kirrel3
Citation: Shennib O, Raines O, Karamian AS and Williams ME (2025) Evaluation of the synapse adhesion molecule Kirrel3 in neurological disease. Front. Neurol. 16:1662931. doi: 10.3389/fneur.2025.1662931
Edited by:
Minerva Carrasquillo, Mayo Clinic Florida, United StatesReviewed by:
Ramachandran Prakasam, Washington University in St. Louis, United StatesLe Wang, University of California, San Diego, United States
Copyright © 2025 Shennib, Raines, Karamian and Williams. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Omar Shennib, b21hci5zaGVubmliQG5ldXJvLnV0YWguZWR1; Megan E. Williams, bWVnYW4ud2lsbGlhbXNAbmV1cm8udXRhaC5lZHU=