Endocrine Abstracts

JOINT2699

Introduction: Congenital Hyperinsulinism (CHI) is the most common cause of hypoglycemia related to inappropriate insulin secretion. More than 30 genes have been identified as contributors to persistent hyperinsulinism, with mutations in the K-ATP channel genes (ABCC8 and KCNJ11) being the most frequently observed in children with severe and persistent forms of the disease.

Aims: To elucidate the genetics of all probands with suspected CHI in Vietnam registered over the past 15 years.

Methods: We included 176 probands with CHI from Vietnam. All probands were screened for variants in the ABCC8 and KCNJ11 genes. Almost patients without mutations in the K-ATP channel genes, next-generation sequencing employing a panel of 28 CHI-related genes was used for analysis, including ABCC8, AKT2, CACNA1C, CACNA1D, CREBBP, DNTTIP1, EP300, FOCAD, FOXA2, GCK, GLUD1, GPC3, HADH, HNF1A, HNF4A, INSR, KCNJ11, KDM6A, KMT2D, MAFA, AGEL2, NSD1, PHOX2B, PMM2, RNF10, SLC16A1 and TRMT10A genes and non-coding regulatory region of HK1. Genetic analysis was performed at the UK University of Exeter Clinical Laboratory.

Results: The genetic cause was identified in 120 out of the 176 CHI patients (68. 1%): 111 had mutations in the K-ATP channel genes (92. 5%), four in GLUD1, three in HNF4A, one in GCK, and one in KMT2D (associated with Kabuki syndrome). As a result, our findings confirm the predominant role of ATP-sensitive potassium channels in the pathogenesis of CHI in Vietnamese patients, with the remaining cases likely attributable to other factors. Furthermore, the ABCC8 gene was found to have the most common pathogenic variants in the K-ATP channel (ABCC8 (n = 103) and KCNJ11 (n = 8)). We also discovered that 55 out of the 111 patients with mutations in the K-ATP channel were either homozygous or compound heterozygous, accounting for half of the cases. We identified 33 distinct variants, with c. 3403-1G>A and c. 2057T>C being the more common mutations in the K-ATP channel genes. One proband had a compound heterozygous pathogenic ABCC8 variant, with one variant inherited from the father (c. 3403-1G>A) and the other (c. 1543G>T) a mutation not identified in the mother. This suggests two possibilities: de novo mutation or germline mosaicism in the mother.

Conclusion: Genetic analysis revealed mutations in over 68 % of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Vietnam. Half of the patients with mutations in the K-ATP channel were either homozygous or compound heterozygous, which means the variant can come from the mother, father, or be de novo.