Genetic and Clinical Characterisation of Congenital Hyperinsulinism: Identification of a Novel ABCC8 Variant

Abstract

Abstract Background: Congenital hyperinsulinism (CHI) is a rare but significant cause of persistent hypoglycemia in neonates and infants. Mutations in several genes, including ABCC8 and KCNJ11, are known to cause CHI. However, data on CHI from our region remain limited. Purpose: To assess the genetic spectrum, clinical characteristics, and outcomes of patients with CHI. Methods: This was a single-centre observational study conducted in the Department of Endocrinology and the Multidisciplinary Research Unit at Sher-i-Kashmir Institute of Medical Sciences, Srinagar, involving six unrelated patients with clinically suspected CHI who underwent detailed clinical evaluation and targeted genetic testing using a 19-gene panel associated with CHI, including hyperinsulinism-hyperammonaemia syndrome. Genetic analysis was performed using Sanger sequencing, followed by parental segregation analysis to determine the inheritance patterns. Results: The mean age at presentation was 24.2 days. Parental consanguinity was present in 3/6 cases. Three patients (50%) presented with hypoglycemic seizures, while the remaining presented with feeding refusal and lethargy. Likely pathogenic variants were identified in three patients (50%). The most commonly affected gene was ABCC8 (n = 2), followed by KCNJ11 (n = 1). Detected ABCC8 variants included a likely novel pathogenic splice variant (c.1009_1011 + 11del) and a frameshift variant (c.453del), whereas the KCNJ11 missense variant identified was c.107 T > A. The likely pathogenic homozygous novel variant, c.1009_1011 + 11del, resulted in a 14 base pair deletion in the intron six and exon six junction of the gene. The mutation affected the invariant GT donor splice site downstream of exon 6 (5 splice). Clinically, two patients responded to diazoxide therapy, while four were classified as diazoxide-unresponsive. Partial pancreatectomy was performed in two of the diazoxide-unresponsive cases. The mean duration of follow-up was 22 months (range: 2-42 months). Conclusion: This study documents a likely novel ABCC8 pathogenic variant from a region with limited prior data on CHI, enhancing global understanding of its genetic diversity. Our findings emphasize the importance of integrating genetic testing into standard diagnostic protocols for timely and tailored interventions. The main limitations of this study include the use of Sanger sequencing as the sole genetic testing approach and the absence of functional validation of the identified variants.