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Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy
  1. Ilse Julia Broekaert1,
  2. Kerstin Becker1,2,
  3. Ingo Gottschalk3,
  4. Friederike Körber4,
  5. Jörg Dötsch1,
  6. Holger Thiele5,
  7. Janine Altmüller5,
  8. Peter Nürnberg5,
  9. Christoph Hünseler1,
  10. Sebahattin Cirak1,2
  1. 1Department of Pediatrics, University Hospital Cologne, Cologne, Germany
  2. 2Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
  3. 3Department of Gynecology, University Hospital Cologne, Cologne, Germany
  4. 4Department of Radiology, University Hospital Cologne, Cologne, Germany
  5. 5Cologne Center for Genomics, University of Cologne, Cologne, Germany
  1. Correspondence to Dr Sebahattin Cirak, Department of Pediatrics, University Hospital Cologne, Cologne 50937, Germany; sebahattin.cirak{at}uk-koeln.de

Abstract

Background Protein-losing enteropathy (PLE) is characterised by gastrointestinal protein leakage due to loss of mucosal integrity or lymphatic abnormalities. PLE can manifest as congenital diarrhoea and should be differentiated from other congenital diarrhoeal disorders. Primary PLEs are genetically heterogeneous and the underlying genetic defects are currently emerging.

Objectives We report an infant with fatal PLE for whom we aimed to uncover the underlying pathogenic mutation.

Methods We performed whole exome sequencing (WES) for the index patient. Variants were classified based on the American College of Medical Genetics and Genomics guidelines. WES results and our detailed clinical description of the patient were compared with the literature.

Results We discovered a novel homozygous stop mutation (c.988C>T, p.Q330*) in the Plasmalemma Vesicle-Associated Protein (PLVAP) gene in a newborn with fatal PLE, facial dysmorphism, and renal, ocular and cardiac anomalies. The Q330* mutation is predicted to result in complete loss of PLVAP protein expression leading to deletion of the diaphragms of endothelial fenestrae, resulting in plasma protein extravasation and PLE. Recently, another single homozygous stop mutation in PLVAP causing lethal PLE in an infant was reported.

Conclusions Our findings validate PLVAP mutations as a cause of syndromic PLE. Prenatal anomalies, severe PLE and syndromic features may guide the diagnosis of this rare disease.

  • congenital diarrhea
  • plvap
  • protein-losing enteropathy
  • syndrome
  • whole exome sequencing

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Footnotes

  • IJB and KB contributed equally.

  • Contributors IJB, KB: acquisition of data; analysis and interpretation of data; drafting of the manuscript. IG, FK: acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. JD: critical revision of the manuscript for important intellectual content. HT: performed bio-informatic analyses of WES data. JA: performed whole exome sequencing and critical revision of the manuscript for important intellectual content. PN: provided whole exome sequencing platform and critical revision of the manuscript for important intellectual content. CH: study concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; study supervision. SC: study concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; administrative, technical or material support; study supervision.

  • Funding SC received funding from the Deutsche Forschungsgemeinschaft Emmy Noether Grant (CI 218/1-1).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Cologne University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Not applicable.

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