1 DOI: 10.4274/jcrpe.galenos.2021.2021.0071 Research article Investigating Genetic Mutations in a Large Cohort of Iranian Patients with Congenital Hyperinsulinism Razzaghy-Azar M et al. Genetic Mutations in Congenital Hyperinsulinism Maryam Razzaghy-Azar 1,2 ; Saeedeh Saeedi 1,3 ; Sepideh Borhan Dayani 1 ; Samaneh Enayati 1 ; Farzaneh Abbasi 4 ; Somayyeh Hashemian 5 ; Peyman Eshraghi 5 ; Siroos Karimdadi 5 ; Parisa Tajdini 4 ; Rahim Vakili 5 ; Mahsa M Amoli 1 ; Hanieh Yaghootkar 6,7,8 1 Metabolic Disorders Research Centre, Endocrinology and Metabolism Molecular – Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran 2 H. Aliasghar Hospital, Iran University of Medical Sciences, Tehran, Iran 3 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran 4 Growth and Development Research Center, Children's Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran 5 Department of Pediatric Diseases, Akbar Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 6 Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK 7 Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK 8 Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden What is already known on this topic? It is well known that CHI is the most frequent cause of severe and persistent hypoglycaemia in the neonatal period, infancy, and childhood. So far, mutations in at least nine different genes have been reported to cause CHI: ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A, SLC16A1, HNF1A and UCP2. Data are mainly limited to European populations while the occurrence of the pathogenic mutations underlying CHI are higher in consanguineous families which are more normal in Asian societies. What this study adds? We will report the frequency of causal gene mutations and also add 5 novel mutations. We surveyed an Iranian population. Screening of HADH gene variants is recommended in all patients with diazoxide-responsive CHI if there is no access to tNGS based on our results. Abstract Objective: Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycaemia from birth. Understanding the pathophysiology and genetic defects behind hyperinsulinism and its complications provides clues to timely diagnosis and management of the disease. This study aimed to evaluate the underlying genetics aetiology of a specific (Iran) cohort with CHI. Method: A total of 44 unrelated children, 20 girls and 24 boys, with an initial diagnosis or history of CHI from all regions of Iran recruited between 2016 and 2019. Targeted next generation sequencing (tNGS) was performed for the genes found in about 50% of CHI patients. Results: Mutations were identified in 24 cases (55%). Patients with a confirmed genetic cause were mainly diagnosed below age of one year old (p=0.01), had less other syndromic features (excluding seizure, p=0.03), were less diazoxide responsive (p=0.04) and were more diazoxide unresponsive leading to pancreatectomy (p=0.007) comparing to those with no identified mutations. Among 24 patients with identified genetic mutations, 17 (71%) had a mutation in ABCC8, 3 patients (12%) in KCNJ11, 3 patients (12%) in HADH, and 1 patient had a mutation in KMT2D. These included five novel mutations in ABCC8, KCNJ11, and KMT2D. Conclusions: This is the biggest genetic study of CHI in Iran. High frequency of recessive forms of CHI, especially HADH mutations, in our study could be due to a high rate of consanguineous marriage. Targeted sequencing of ABCC8/ KCNJ11 in diazoxide unresponsive cases is recommended. Keywords: Congenital hyperinsulinism, genetic mutations, Diazoxide, tNGS Corresponding authors: uncorrected proof