AUTHOR=Lee Cheng-Ting , Tsai Wen-Hao , Chang Chien-Ching , Chen Pei-Chun , Fann Cathy Shen-Jang , Chang Hsueh-Kai , Liu Shih-Yao , Wu Mu-Zon , Chiu Pao-Chin , Hsu Wen-Ming , Yang Wei-Shiung , Lai Ling-Ping , Tsai Wen-Yu , Yang Shi-Bing , Chen Pei-Lung 

TITLE=Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1283907

DOI=10.3389/fendo.2023.1283907

ISSN=1664-2392

ABSTRACT=<sec><title>Objective</title><p>Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations.</p></sec><sec><title>Methods</title><p>We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (K<sub>ATP</sub>) channel variants were assessed using patch clamp recording and Western blot.</p></sec><sec><title>Results</title><p>Nine of 13 (69%) patients with ten different pathogenic variants (7 in <italic>ABCC8</italic>, 2 in <italic>KCNJ11</italic> and 1 in <italic>GCK</italic>) were identified by the combined sequencing. The variant <italic>ABCC8</italic> p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F K<sub>ATP</sub> channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C K<sub>ATP</sub> channels were defective in trafficking. One patient had a <italic>de novo</italic> dominant mutation in the <italic>GCK</italic> gene (p.I211F), and WES revealed mosaicism of this variant from another patient.</p></sec><sec><title>Conclusion</title><p>Pathogenic variants in K<sub>ATP</sub> channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the <italic>ABCC8</italic> gene is highly suggestive of a founder effect. The I211F mutation in the <italic>GCK</italic> gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) K<sub>ATP</sub> channels are also associated with the diazoxide-unresponsive phenotype.</p></sec>