Iddo Vardi1,2,3, Ortal Barel2,3, Michal Sperber2,3, Michael Schvimer2,4, Moran Nunberg1,2, Michael Field5, Jodie Ouahed5,6, Dina Marek-Yagel2,7, Lael Werner1,2, Yael Haberman1,2, Avishay Lahad1,2, Yair Anikster2,7, Gideon Rechavi2,3, Iris Barshack2,4, Joshua J McElwee8, Joseph Maranville8, Raz Somech2,9,10, Scott B Snapper5,6,11, Batia Weiss1,2, Dror S Shouval12,13,14. 1. Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Sheba Road 2, 5262100, Tel Hashomer, Israel. 2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3. Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel. 4. Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel. 5. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA. 6. Harvard Medical School, Boston, MA, USA. 7. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel. 8. Merck Research Laboratories, Merck and Co, Boston, MA, USA. 9. Pediatric Immunology Service, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel. 10. Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel. 11. Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA. 12. Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Sheba Road 2, 5262100, Tel Hashomer, Israel. dror.shouval@gmail.com. 13. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. dror.shouval@gmail.com. 14. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA. dror.shouval@gmail.com.
Abstract
BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis. METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function. RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface. CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.
BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis. METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function. RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface. CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.
Authors: Isobel A Smith; Brittany R Knezevic; Johannes U Ammann; David A Rhodes; Danielle Aw; Donald B Palmer; Ian H Mather; John Trowsdale Journal: J Immunol Date: 2010-03-05 Impact factor: 5.422
Authors: Holm H Uhlig; Tobias Schwerd; Sibylle Koletzko; Neil Shah; Jochen Kammermeier; Abdul Elkadri; Jodie Ouahed; David C Wilson; Simon P Travis; Dan Turner; Christoph Klein; Scott B Snapper; Aleixo M Muise Journal: Gastroenterology Date: 2014-07-21 Impact factor: 33.883
Authors: Ioannis Xinias; Antigoni Mavroudi; Dimitrios Mouselimis; Anastasios Tsarouchas; Konstantina Vasilaki; Ioannis Roilides; Florence Lacaille; Olga Giouleme Journal: SAGE Open Med Case Rep Date: 2018-10-30