Integrated genetic and functional analyses reveal the pathogenic effects of a novel STXBP3 variant in very-early-onset inflammatory bowel disease with immunodeficiency
- 1Department of Gastroenterology, Children’s Hospital of Fudan University, National Children’s Medical Center
- 2Center of Molecular Medicine, Pediatrics Research Institute, Children’s Hospital of Fudan University, National Children’s Medical Center
Abstract
Background: Very early onset inflammatory bowel disease (VEOIBD) is frequently driven by monogenic defects. Pathogenic variants in the syntaxin-binding protein 3 ( STXBP3 ) gene have been implicated in VEOIBD; however, the relationship between specific variant types and clinical manifestations remains incompletely understood. This study aimed to identify the genetic cause in a patient with VEOIBD and explore the possible genotype-phenotype correlations of STXBP3 -related disorders.
Methods: We performed trio-whole-exome sequencing (trio-WES) on a male infant presenting with VEOIBD, sensorineural hearing loss, and immunodeficiency. Functional consequences of the identified variant were investigated using RNA sequencing (RNA-seq), reverse transcription-polymerase chain reaction (RT-PCR), western blotting and co-immunoprecipitation (co-IP) assay. A systematic literature review was conducted to analyze clinical features and inheritance patterns across all reported STXBP3 cases.
Results: A novel heterozygous splice-site variant in STXBP3 (c.1022_1029 + 3del) was identified. RNA-seq and RT-PCR confirmed that this variant causes aberrant splicing, leading to the skipping of exon 12 and the production of a truncated protein. Co-IP showed that the aberrant protein reduced the ability to bind STX4. The comprehensive analysis of 13 patients revealed possible genotype-phenotype correlations: splice-site and frameshift variants were observed predominantly follow an autosomal dominant (AD) pattern associated with VEOIBD, sensorineural hearing loss, and immunodeficiency; conversely, missense variants generally follow an autosomal recessive (AR) pattern linked to VEOIBD, and congenital malformations. Given the small cohort, these comparisons were descriptive and were not intended to establish definitive genotype–phenotype associations.
Conclusions: We identified a novel pathogenic STXBP3 variant and validated its impact on its function. The observed differences between AD and AR cases provided a preliminary, hypothesis-generating framework for understanding STXBP3-related disease, which require validation in larger cohorts.
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BibTeX
@article{pan2026integrated,
title = {{Integrated genetic and functional analyses reveal the pathogenic effects of a novel STXBP3 variant in very-early-onset inflammatory bowel disease with immunodeficiency}},
author = {Chun Pan and Ping Zhang and Wenjuan Tang and Shengnan Wang and Zhiheng Huang and Xiaolan Lu and Yingying Meng and Haijiao Xia and Lin Wang and Ying Huang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1871633},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1871633/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated genetic and functional analyses reveal the pathogenic effects of a novel STXBP3 variant in very-early-onset inflammatory bowel disease with immunodeficiency
AU - Chun Pan
AU - Ping Zhang
AU - Wenjuan Tang
AU - Shengnan Wang
AU - Zhiheng Huang
AU - Xiaolan Lu
AU - Yingying Meng
AU - Haijiao Xia
AU - Lin Wang
AU - Ying Huang
PY - 2026
DA - 2026/10/05
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1871633
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1871633/full
AB - Background: Very early onset inflammatory bowel disease (VEOIBD) is frequently driven by monogenic defects. Pathogenic variants in the syntaxin-binding protein 3 ( STXBP3 ) gene have been implicated in VEOIBD; however, the relationship between specific variant types and clinical manifestations remains incompletely understood. This study aimed to identify the genetic cause in a patient with VEOIBD and explore the possible genotype-phenotype correlations of STXBP3 -related disorders. Methods: We performed trio-whole-exome sequencing (trio-WES) on a male infant presenting with VEOIBD, sensorineural hearing loss, and immunodeficiency. Functional consequences of the identified variant were investigated using RNA sequencing (RNA-seq), reverse transcription-polymerase chain reaction (RT-PCR), western blotting and co-immunoprecipitation (co-IP) assay. A systematic literature review was conducted to analyze clinical features and inheritance patterns across all reported STXBP3 cases. Results: A novel heterozygous splice-site variant in STXBP3 (c.1022_1029 + 3del) was identified. RNA-seq and RT-PCR confirmed that this variant causes aberrant splicing, leading to the skipping of exon 12 and the production of a truncated protein. Co-IP showed that the aberrant protein reduced the ability to bind STX4. The comprehensive analysis of 13 patients revealed possible genotype-phenotype correlations: splice-site and frameshift variants were observed predominantly follow an autosomal dominant (AD) pattern associated with VEOIBD, sensorineural hearing loss, and immunodeficiency; conversely, missense variants generally follow an autosomal recessive (AR) pattern linked to VEOIBD, and congenital malformations. Given the small cohort, these comparisons were descriptive and were not intended to establish definitive genotype–phenotype associations. Conclusions: We identified a novel pathogenic STXBP3 variant and validated its impact on its function. The observed differences between AD and AR cases provided a preliminary, hypothesis-generating framework for understanding STXBP3-related disease, which require validation in larger cohorts.
SN - 1664-3224
ER -