A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene

PurposeWe sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause.MethodsExome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed.ResultsWe identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes.ConclusionWe describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

SP7.1.16 Endoscopy and biopsy for chronic diarrhoea: an audit and cost analysis

Aims The aim of the study is to analyse the costs of performing diagnostic endoscopy with histopathological sampling for patients suffering with chronic or persistent diarrhoea. Methods 300 patients were identified who required an endoscopy in 2019 according to the British Society of Gastroenterology guidelines. Patient’s presenting complaint, endoscopic and histological diagnosis and follow up plans were noted. 147 patients were included into our study whose presenting complaint was solely chronic or persistent diarrhoea. Those who presented with acute diarrhoea, PR bleeding or other concomitant indication for lower gastrointestinal endoscopy were excluded. Data from the national schedule of NHS costs was used to calculate expenditure. Results The total expenditure calculated for the 147 patients was £55,973. There was a total of 126 colonoscopies and 21 flexible sigmoidoscopies performed by the department. The number of patients who received medical treatment following endoscopy was 13/147 (9%) 8 of whom had nonspecific colitis on histology. There were 29 patients (20%) who required symptomatic treatment and there were 98 patients (66%) who received no intervention or were discharged immediately and 7 patients (5%) that required surgical intervention. The total cost of procedures not leading to surgical or medical management with steroids or immunomodulators was £47733 which is 85.3% of the total expenditure. Conclusion A significantly large proportion of investigations lead to no intervention or symptomatic treatment of the patient. Given this lack of diagnostic yield and financial burden, there could be room for advancement in the current guidelines for managing persistent diarrhoea.

TP1.2.1SeHCAT scan as an investigation for chronic diarrhoea; a single trust experience

Introduction: Recent published (British Society of Gastroenterology) guidelines strongly recommended investigating unexplained chronic loose stools with SeHCAT scans when available rather than empirical treatment. SeHCAT scan was introduced at our trust in 2015. We aimed to audit this locally. Methods All SeHCAT scans that were done at our trust trust from Jan 2015 to March 2020 were included. Patient demographics along with risk factors and duration of symptoms were documented as well as the referred speciality. Results 55 patients were identified. Average age at time of diagnosis was 50y (18-70y). M:F was 1:3.2 . Most scans were requested by the oncology team as part of the “pelvic radiotherapy late effects service” (n = 25), followed by the gastroenterology team (n = 22) and general surgery team (n = 8). The mean duration of symptoms was 4 years. 73% of the scans showed evidence of bile acid malabsorption (BAM) (n = 40) with bile retention <15%, with the majority of them (n = 30) having severe BAM (retention <5%). 60% of the patients had at least one lower GI endoscopy as part of their workup. The majority of patients were found to have type 3 BAM (n = 37). 60% of patients had symptom improvement on either diet alone or with bile-acid sequestrants (n = 23) and were discharged. Conclusion: SeHCAT scan is a useful test to investigate unexplained chronic diarrhoea. It is important to identify patients at risk of developing bile acid malabsorption. It is currently underutilized by our trust, which might be because of funding issues and awareness among clinicians.