ESPE Abstracts

Background: Diazoxide (DZX) is the first-line drug for congenital hyperinsulinism (CHI). DZX-unresponsiveness is common in patients with ATP-sensitive K (KATP) channel (ABCC8, KCNJ11) gene abnormalities. However, even in KATP channel abnormalities, when pathological variants are found only in the paternal allele, the pancreatic lesions may be localized and radically resectable, and genetic analysis may be helpful. Some reports summarizing the genetic background of CHI in Europeans and Americans have been published, but few reports have been made on Asians.

Objective: To clarify the genetic background of CHI in Japanese patients.

Methods: The following genes were analyzed using the Sanger method or next-generation sequencing (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, INSR, HK1). Deletions and duplications of GCK, HNF1A, and HNF4A genes were also analyzed using the MLPA method. Pathogenicity evaluation of variants was performed according to ACMG/AMP guidelines. Pathogenic variants were defined as Pathogenic (P)/Likely Pathogenic (LP).

Results: P/LP variants (P/LP group) were observed in 99 patients (65%), including 68 patients (69%) with ABCC8, 13 (13%) with GLUD1, 9 (9%) with KCNJ11, 7 (7%) with HNF4A, 2 (2%) with GCK, and 53 patients (55%) have new variants in the P/LP group. In the P/LP group of DZX-unresponsive patients (46 patients) with a known history, the ABCC8/KCNJ11 variant was identified in 45 patients (99%). Nine of the 45 patients (20%) had variants in both alleles, 35 patients (78%) had variants in one allele, and one patient (1%) had de novo variant. The c.2992C>T variant was the most common variant detected, and 90% (9/10) were DZX-unresponsive.

Discussion: This study included the largest cohort of Asian CHI. P/LP variants were identified in 65% of the total. Several novel Japanese-specific pathological variants were observed. Focal lesions were lower in the Japanese population (25%) compared to Westerners (75%). The c.2992C>T variant may help predict DZX-unresponsiveness.

Conclusion: This study is Asia's most extensive cohort-based CHI genetic analysis study. For the first time, we found that the genetic background of Japanese CHI differs from that of Western countries.