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

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.

Cilia Ultrastructure Associated with Primary Ciliary Dyskinesia in Omani Patients.

Objectives: Primary ciliary dyskinesia (PCD) is a disorder affecting the structure and function of the motile cilia of the respiratory system. Transmission electron microscopy is one method that can be used to examine ciliary ultrastructure in airway biopsies. Although the role of ultrastructural findings in PCD has been described in the literature, this role has not been well-studied in the Middle East or, specifically, Oman. This study aimed to describe ultrastructural features in Omani patients with high suspicion of PCD. Methods: This retrospective cross-sectional study included 129 adequate airway biopsies obtained from Omani patients attending pulmonary clinics at Sultan Qaboos University Hospital and the Royal Hospital, Muscat, Oman, from 2010 to 2020 who were suspected of having PCD. Results: Ciliary ultrastructural abnormalities in the current study population were outer dynein arm (ODA) associated with inner dynein arm (IDA) defects (8%), microtubular disorganisation associated with IDA defect (5%) and isolated ODA defect (2%). Most of the biopsies showed normal ultrastructure (82%). Conclusion: In Omani patients suspected to have PCD, normal ultrastructure was the most common feature.

Ivacaftor in Omani children with cystic fibrosis caused by p.Ser549Arg CFTR mutation.

Background: Cystic fibrosis (CF) is a multisystemic chronic disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. These mutations are classified in to six classes. Ivacaftor is a CFTR potentiator which partially restores the CFTR function for class III mutations. In Oman, p.Ser549Arg (class III) is the most common mutation (65% of cases). Our study prospectively evaluated the tolerance and clinical efficacy of ivacaftor. Methods: A prospective observational study was conducted at the Royal Hospital, Oman. All children aged 6-18 years who are followed and carry at least one copy of the p.Ser549Arg mutation were started on Ivacaftor and included in the study. Data collected included weight, height, forced expiratory volume in first second (FEV1), sweat chloride concentration, stool elastase level and liver enzymes at baseline and at 12, 24, 36, and 48 weeks after initiation of treatment. The number of CF pulmonary exacerbations one year before and during treatment were compared. Results: Twenty one children were started on Ivacaftor (90% homozygous for p.Ser549Arg). The mean age was 10.8 (SD ±3.5) years. When compared to baseline, FEV1 significantly improved by a mean of 10.8 (SD ±13.5) percentage points (pp) and 14.3 (SD ±7.5) pp at 12 and 48 weeks respectively. The sweat chloride level significantly dropped from a mean of 107 (SD ±8.5) mmol/l to 38.5 (SD ±22.3) mmol/l at 12 weeks and remained low. The Body Mass Index (BMI) improved by a mean of 1.37 (SD ±1.3) kg/m 2 and 1.9 (SD ±1.35) kg/m 2 at 24 and 48 weeks of treatment respectively. The number of admissions the year before and during treatment reduced significantly from a mean of 2.2 (SD± 1.9) to 0.7 (SD ±1) admission per year. Two children developed transaminitis. Conclusion: Ivacaftor is well tolerated and resulted in a significant improvement in FEV1, BMI and sweat chloride level in children with p.Ser549Arg CFTR mutation.

Prevalence and Characteristics of Cystic Fibrosis in Omani Children: A Multi-center Cross-sectional Study.

Objectives: To describe the demographic distribution of cystic fibrosis (CF) in Omani children, estimate the national prevalence, and provide updated mutational panels of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Methods: We conducted a retrospective cross-sectional study of all CF patients who had been diagnosed and followed-up at Sultan Qaboos University Hospital and Royal Hospital in Oman between 2006 and 2020. Data were collected from electronic hospital records and telephone interviews. Results: A total of 227 patients with CF were included in the study. Geographical clusters of the disease were identified in the governorates of Al-Batinah, A'Dhahirah, and A'Dakhiliyah. Parental consanguinity and family history of CF were present in 68.3% and 69.6% of the patients, respectively. The most common CFTR mutation was p.Ser549Arg (52.0%), followed by p.Phe508del (12.3%), and c.2988+1G>A (4.4%). Three novel CFTR mutations were identified, viz., Leu88TyrFs*, p.Asp192Val, and c.4242+1G>C. Conclusions: The estimated prevalence of CF in Oman is 10.3 per 100 000 individuals. Premarital genetic counseling and preimplantation genetic testing are recommended in CF-prevalent regions.