Digestive Diseases and Sciences

, Volume 63, Issue 5, pp 1192–1199 | Cite as

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
Original Article

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.

Keywords

Congenital diarrhea VEOIBD SKIV2L Primary immunodeficiency Epithelial cells 

Notes

Acknowledgments

D.S.S. is supported by the Israel Science Foundation, the Israel-US Bi-national Science Foundation and Jeffery Modell Foundation grants. S.B.S. is supported by NIH Grants HL59561, DK034854, and AI50950, the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interests to disclose.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Iddo Vardi
    • 1
    • 2
    • 3
  • Ortal Barel
    • 2
    • 3
  • Michal Sperber
    • 2
    • 3
  • Michael Schvimer
    • 2
    • 4
  • Moran Nunberg
    • 1
    • 2
  • Michael Field
    • 5
  • Jodie Ouahed
    • 5
    • 6
  • Dina Marek-Yagel
    • 2
    • 7
  • Lael Werner
    • 1
    • 2
  • Yael Haberman
    • 1
    • 2
  • Avishay Lahad
    • 1
    • 2
  • Yair Anikster
    • 2
    • 7
  • Gideon Rechavi
    • 2
    • 3
  • Iris Barshack
    • 2
    • 4
  • Joshua J. McElwee
    • 8
  • Joseph Maranville
    • 8
  • Raz Somech
    • 2
    • 9
    • 10
  • Scott B. Snapper
    • 5
    • 6
    • 11
  • Batia Weiss
    • 1
    • 2
  • Dror S. Shouval
    • 1
    • 2
    • 5
  1. 1.Pediatric Gastroenterology UnitEdmond and Lily Safra Children’s Hospital, Sheba Medical CenterTel HashomerIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Cancer Research CenterSheba Medical CenterTel HashomerIsrael
  4. 4.Institute of PathologySheba Medical CenterTel HashomerIsrael
  5. 5.Division of Gastroenterology, Hepatology and NutritionBoston Children’s HospitalBostonUSA
  6. 6.Harvard Medical SchoolBostonUSA
  7. 7.Metabolic Disease UnitEdmond and Lily Safra Children’s HospitalTel HashomerIsrael
  8. 8.Merck Research LaboratoriesMerck and CoBostonUSA
  9. 9.Pediatric Immunology ServiceEdmond and Lily Safra Children’s HospitalTel HashomerIsrael
  10. 10.Jeffrey Modell Foundation CenterEdmond and Lily Safra Children’s HospitalTel HashomerIsrael
  11. 11.Division of Gastroenterology, Hepatology and EndoscopyBrigham and Women’s HospitalBostonUSA

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