PT  - JOURNAL ARTICLE
AU  - Aida Bertoli-Avella
AU  - Ronja Hotakainen
AU  - Maryam Al Shehhi
AU  - Alice Urzi
AU  - Catarina Pareira
AU  - Anett Marais
AU  - Khoula Al Shidhani
AU  - Sumaya Aloraimi
AU  - Galina Morales-Torres
AU  - Steffen Fisher
AU  - Laura Demuth
AU  - Laila Abdel Moteleb Selim
AU  - Nihal Al Menabawy
AU  - Maryam Busehail
AU  - Mohammed AlShaikh
AU  - Naser Gilani
AU  - Dler Nooruldeen Chalabi
AU  - Nasser S Alharbi
AU  - Majid Alfadhel
AU  - Mohammed Abdelrahman
AU  - Hanka Venselaar
AU  - Nadeem Anjum
AU  - Anjum Saeed
AU  - Malak Ali Alghamdi
AU  - Hamad Aljaedi
AU  - Hisham Arabi
AU  - Vasiliki Karageorgou
AU  - Suliman Khan
AU  - Zahra Hajjari
AU  - Mandy Radefeldt
AU  - Ruslan Al-Ali
AU  - Kornelia Tripolszki
AU  - Amer Jamhawi
AU  - Omid Paknia
AU  - Claudia Cozma
AU  - Huma Cheema
AU  - Najim Ameziane
AU  - Saleh Al-Muhsen
AU  - Peter Bauer
TI  - A disorder clinically resembling cystic fibrosis caused by biallelic variants in the <em>AGR2</em> gene
AID  - 10.1136/jmedgenet-2021-108150
DP  - 2021 Dec 24
TA  - Journal of Medical Genetics
PG  - jmedgenet-2021-108150
4099  - http://jmg.bmj.com/content/early/2021/12/23/jmedgenet-2021-108150.short
4100  - http://jmg.bmj.com/content/early/2021/12/23/jmedgenet-2021-108150.full
AB  - Purpose We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause.Methods Exome/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.Results We 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.Conclusion We 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.Data are available upon reasonable request. Data are available on request.