1 - Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children’s Hospital, and Harvard Medical School, Boston, MA, 02115, USA
2 - Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA c
3 - Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
4 - Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA
5 - Department of Biomedical Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
6 - Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
7 - Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
8 - Division of Gastroenterology, Hepatology, and Nutrition, Children’s Mercy Hospital, Kansas City, MO, 64108, USA
9 - Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
10 - Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
11 - Primary Immunodeficiencies Unit; Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal
12 - CEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, 1150, Portugal
13 - Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal
14 - Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA; Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA
15 - Department of Genetics, Yale University, New Haven, CT, 06510, USA
16 - F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
17 - Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
18 - Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
19 - Program in Immunology, Harvard Medical School, Boston, MA, 02115, USA
20 - Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
21 - Division of Emergency Medicine, Department of Pediatrics, Boston Children’s Hospital, and Harvard Medical School, Boston, MA, 02115, USA
22 - Dr. von Hauner Children’s Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, 80337, Germany
23 - Department of Pediatrics, Nemours Children’s Specialty Care, Jacksonville, FL 32207, USA
24 - SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
25 - Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
26 - Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK
27 - Children’s Immunology Service, Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, NE1 4LP, UK
28 - Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, G51 4TF, UK
29 - Division of Human Genetics, The Children’s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Department of Molecular Medicine, University Sapienza, Rome, 00189, Italy
30 - Division of Rheumatology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
31 - Division of Gastroenterology, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA
- Journal of Crohn's and Colitis, 2021, 1–12
- doi:10.1093/ecco-jcc/jjab077
Resumo:
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 aetiologies 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 aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed.
Results: In each of the ten patients, we identified damaging heterozygous or biallelic variants in the 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 lead 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.
Palavras Chave: VEOIBD; sensorineural hearing loss; STXBP3