Molecular Genetic Spectrum and Clinical Correlates of Congenital Hyperinsulinism in India: A Multicentric Cross-sectional Study

Introduction: Congenital Hyperinsulinism (CHI) is a rare genetic disorder of pancreatic β-cells characterised by persistent hypoglycaemia resulting from inappropriate insulin secretion. Such recurrent hypoglycaemic episodes are often associated with irreversible neurological injury and long-term developmental impairment, underscoring the importance of timely diagnosis and initiation of targeted therapy to improve neurodevelopmental outcomes and quality of life. In India, the true burden of CHI remains uncertain due to limited awareness, diagnostic delays, fragmented care pathways and restricted access specialised centers compounded by the absence of a national surveillance system. Consequently, many infants undergo prolonged empirical medical therapy or delayed surgical intervention, leading to preventable complications and adverse outcomes. Aim: The present study was undertaken to evaluate the molecular genetic spectrum and clinical correlates of CHI, determine the frequency and distribution of pathogenic variants, assess genotype-phenotype associations, and interpret their implications for management. Materials and Methods: The current multi-centric crosssectional study was conducted from July 2022 to December 2025 at Pramukhswami Medical College and Shri Krishna Hospital, Karamsad, Gujarat, India. Eighteen (n =18) children with biochemically confirmed CHI were recruited through coordinated CHI India Association-linked clinics and outreach programs across India. Clinical, biochemical, and treatment details were recorded. Genetic testing was performed using Next-Generation Sequencing (NGS) panels at accredited laboratories including the Madras Diabetes Research Foundation. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria. Clinical and genetic data were summarised using descriptive statistics, and genotype-phenotype associations were assessed using the Kruskal-Wallis test. Results: Pathogenic or likely pathogenic variants were detected in all 18 children (100%). Mutations involved ABCC8 (n=11), KCNJ11 (n=3), HNF4α (n=2), GLUD1 (n=1), and PMM2 (n=1). Eight (44%) were diazoxide-responsive, seven (39%) unresponsive, and three (17%) partially responsive. Five children (27.8%) underwent surgery; focal lesions were confirmed in those with paternally inherited ABCC8/KCNJ11 mutations. Median birth-weight SDS differed significantly across genotypes (Kruskal-Wallis H=13.04, p=0.023). Neurodevelopmental delay was present in 27.77% of patients. Conclusion: Genetic testing provides high diagnostic yield in Indian children, with ABCC8 and KCNJ11 mutations predominating. Paternal KATP mutations predict focal disease and potential surgical cure. Early molecular diagnosis and optimised therapy are crucial for improved outcomes.