TBA (22W104)

PERCC1 – associated Congenital Diarrhoea – A Novel Cause of Intestinal Failure.

Author(s)

Emily Stenke1, Cara Dunne1,2, Dina Marek-Yagel3,4,5, Ben Pode-Shakked3,5,6, Ellen Crushell7, Anthea Bryce-Smith1, Michael McDermott8, Maureen J. O’Sullivan8, Alvit Veber3, Mansa Krishnamurthy,9,10, James M. Wells6,9,10, Yair Anikster3,4,11, Billy Bourke1,12

Department(s)/Institutions

1 National Centre for Paediatric Gastroenterology, Children’s Health Ireland-Crumlin, Dublin, Ireland. 2 Department of Gastroenterology, St James' Hospital, Dublin, Ireland. 3 Metabolic Disease Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. 4 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 5 Clalit Research Institute, Ramat Gan, Israel. 6 Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 7 National Centre for Inherited Metabolic Disorders, Children’s Health Ireland-Temple Street, Dublin, Ireland 8 Department of Histopathology, Children's Health Ireland-Crumlin, Dublin, Ireland. 9 Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA. 10 Division of Endocrinology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA. 11 The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. 12 School of Medicine, University College Dublin, Dublin, Ireland.

Introduction

Congenital diarrhoeas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with chronic diarrhoea and intestinal failure. We describe identical homozygous mutations in a novel gene (PERCC1) in two unrelated Irish patients with idiopathic congenital diarrhoea. The affected protein is essential for entero-endocrine function, offering the potential for treatment using enteric hormone analogues for this intractable condition.

Aims/Background

To determine whether mutations in the recently annotated PERCC1 were present in two unrelated Irish patients attending the intestinal failure programme at CHI-Crumlin/St James Hospital with idiopathic congenital diarrhoea requiring home parenteral nutrition.

Method

Currently 12- and 19-years old, these male patients presented with watery diarrhoea and hypernatraemic dehydration in infancy, with no cause identified despite comprehensive clinical investigations, and whole exome sequencing was negative. PCR and Sanger sequencing of the entire coding region and intron boundaries of PERCC1 were performed for each patient and their parents, and gastrin levels were analysed.

Results

In both patients, serum gastrin levels were low despite a meal challenge. Sequencing of the PERCC1 gene revealed a novel shared homozygous c.390C>G stop gain variant.

Conclusions

We present two unrelated patients harbouring a shared homozygous variant in PERCC1, comprising the first description of a point mutation in this gene. That both of only 2 parenteral nutrition dependent children/young adults with unexplained diarrhoea at our institution harboured a PERCC1 mutation suggests that PERCC1-associated enteropathy may be a common cause of CODEs in intestinal failure programmes worldwide and highlights the importance of its inclusion in exome sequencing interpretation.