Clinical utility of genomic investigations in a Middle Eastern pediatric gastroenterology disease cohort

BACKGROUND The landscape and clinical utility of comprehensive genomic investigations for a wide range of pediatric gastrointestinal (GI) disorders have not been fully characterized in the Middle East. AIM To characterize the diagnostic yield and clinical utility of genomic investigations in a Middle Eastern pediatric cohort of GI disorders, and to dissect the pathogenic landscape of those disorders in this region. METHODS Sixty-nine pediatric patients of diverse Arab and Asian origins, were clinically and genetically assessed for a spectrum of GI diseases, including liver disease, inflammatory bowel disease, chronic diarrhea, and pancreatitis. Clinical genomic investigations included mainly (87%) next generation sequencing-based gene panels and whole exome or genome sequencing. Clinical information, including demographics, symptoms, management and clinical outcomes, was extracted from medical records. RESULTS The overall positive yield was 55%, whereas multiple molecular diagnoses were made in 3 patients (4%) including 2 with triple genetic findings, highlighting the utility of genetic investigations in delineating the phenotypic complexity in this cohort. A secondary medically actionable finding (MYBPC3 -associated cardiomyopathy) was identified in one out of 12 patients (8%) who received exome or genome sequencing. Among all disease groups, the diagnostic yield was highest in patients with chronic diarrhea (73.3%) followed by those with cholestasis (62.5%). Copy number variants contributed substantially (18%) to the pathogenic variation spectrum. Consistent with consanguinity rates in this region, autosomal recessive conditions accounted for 66% of all diagnosed patients. Importantly, genetic findings guided clinical management plans and interventions in most cases (97%). Finally, we highlight a putative candidate gene, NR1I3 , possibly associated with cholestasis identified in an undiagnosed Yemeni family with episodic transient disease. CONCLUSION Our study provides new insights into the pathogenic variation landscape in pediatric GI disorders in the Middle East and emphasizes the clinical utility of genomic investigations in managing those patients.