Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome

Iddo Vardi, Ortal Barel, Michal Sperber, Michael Schvimer, Moran Nunberg, Michael Field, Jodie Ouahed, Dina Marek-Yagel, Lael Werner, Yael Haberman, Avishay Lahad, Yair Anikster, Gideon Rechavi, Iris Barshack, Joshua J. McElwee, Joseph Maranville, Raz Somech, Scott B. Snapper, Batia Weiss, Dror S. Shouval*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1192-1199
Number of pages8
JournalDigestive Diseases and Sciences
Issue number5
StatePublished - 1 May 2018


FundersFunder number
Bi-national Science Foundation and Jeffery Mod-ell Foundation
Israel-US Bi-national Science Foundation
National Institutes of HealthDK034854, HL59561
National Institute of Allergy and Infectious DiseasesR01AI050950
Leona M. and Harry B. Helmsley Charitable Trust
Israel Science Foundation


    • Congenital diarrhea
    • Epithelial cells
    • Primary immunodeficiency
    • SKIV2L
    • VEOIBD


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