Variants in STXBP3 Are Associated With Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation

Jodie Ouahed, Judith R Kelsen, Waldo A Spessott, Kameron Kooshesh, Maria L Sanmillan, Noor Dawany, Kathleen E Sullivan, Kathryn Hamilton, Voytek Slowik, Sergey Nejentsev, João Farela Neves, Helena Flores, Wendy K Chung, Ashley Wilson, Kwame Anyane Yeboa, Karen Wou, Preti Jain, Michael Field, Sophia Tollefson, Maiah H DentDalin Li, Takeo Naito, Dermot P B McGovern, Andrew C Kwong, Faith Taliaferro, Jose Ordovas-Montanes, Bruce Horwitz, Daniel Kotlarz, Christoph Klein, Jonathan Evans, Jill Dorsey, Neil Warner, Abdul Elkadri, Aleixo M Muise, Jeffrey Goldsmith, Benjamin Thompson, Karin R Engelhardt, Andrew J Cant, Sophie Hambleton, Andrew Barclay, Agnes Toth-Petroczy, Dana Vuzman, Nikkola Carmichael, Corneliu Bodea, Christopher A Cassa, Marcella Devoto, Richard L Maas, Edward M Behrens, Claudio G Giraudo, Scott B Snapper

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


BACKGROUND AND AIMS: Very early onset inflammatory bowel disease (VEOIBD) is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic etiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation.

METHODS: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss, and, in the majority, recurrent infections. Genetic etiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on PBMCs and functional studies with epithelial cell lines were employed.

RESULTS: In each of the 10 patients, we identified damaging heterozygous or biallelic variants in Syntaxin-Binding Protein 3 gene (STXBP3), a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and led to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity.

CONCLUSION: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

Original languageEnglish
Pages (from-to)1908–1919
Issue number11
Early online date23 Apr 2021
Publication statusPublished - Nov 2021


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