Mutational analysis of <i>ABCC8</i>, <i>KCNJ11</i>, <i>GLUD1</i>, <i>HNF4A</i> and <i>GCK</i> genes in 30 Chinese patients with congenital hyperinsulinism

Abstract

We conducted a cohort study to elucidate the molecular spectrum of congenital hyperinsulinism (CHI) in Chinese pediatric patients. Thirty Chinese children with CHI were chosen as research subjects, 16 of whom were responsive to diazoxide and 13 of whom were not (1 patient was not given the drug for medical reasons). All exons of the adenosine triphosphate (ATP)-sensitive potassium channel (KATP channel) genes KCNJ11 and ABCC8, the hepatocyte nuclear factor 4 α (HNF4A) gene, and the Glucokinase (GCK) gene as well as exons 6 and 7 and 10-12 of the glutamate dehydrogenase 1 (GLUD1) gene were amplified from genomic DNA and directly sequenced. Mutations were identified in 14 of 30 patients (47%): 3 in GLUD1 (10%) and 11 in the KATP channel genes (37%). Six patients had paternally derived monoallelic KATP channel mutations predictive of the focal CHI form. We found a novel de novo ABCC8 mutation, p. C1000*, a novel paternally inherited ABCC8 mutation, D1505H, and a dominantly inherited ABCC8 mutation, R1217K. The GLUD1 activating mutation R269H was found in 2 patients: 1 de novo and the other paternally inherited. A de novo S445L mutation was found in 1 patient. No significant HNF4A or GCK mutations were found. CHI has complex genetic onset mechanisms. Paternally inherited monoallelic mutations of ABCC8 and KCNJ11 are likely the main causes of KATP-CHI in Chinese patients. Glutamate dehydrogenase-CHI is the second most common cause of CHI, while HNF4A and GCK are rare types of CHI in Chinese patients.

Congenital Hyperinsulinism in China: A Review of Chinese Literature Over the Past 15 Years

“…A total of 207 cases, 1 case from our own department together with the 206 cases of CHI reported previously from China ( 11 , 12 , 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ) were available for analysis. Among them, 154 cases were from Beijing city, 32 from Shanghai city, 14 from Guangdong province, 4 from Zhejiang province, and 1 case each from Hunan, Sichuan, and Shandong provinces.…”

“…Therefore, it is important to diagnose and treat these infants with CHI at the earliest to alleviate the degree of brain damage. Several studies ( 10 , 11 , 12 , 13 ) have already summarized the clinical and genetic characteristics of CHI in Beijing and Shanghai; however, studies throughout China are yet lacking. In this article, we aimed to review the present knowledge on the clinical presentation, therapeutic outcomes, and genetic mutations of CHI in the Chinese population and to compare this knowledge with that in other countries.…”

Clinical Management and Gene Mutation Analysis of Children with Congenital Hyperinsulinism in South China

“…In this study, we reported the clinical characteristics, laboratory data and genetic features of 65 patients with CHI, which was the largest CHI cohort in southern China. Until now, there have been no nationwide data regarding this disorder in China, although several studies have summarized the clinical and genetic characteristics of CHI in northern and eastern China (20,21,22).…”

Clinical and Molecular Spectrum of Glutamate Dehydrogenase Gene Defects in 26 Chinese Congenital Hyperinsulinemia Patients

“…Until now, nine Chinese GDH-HI patients have been reported in four different studies [ 5 – 8 ]. However, little is known about clinical characteristics, long-term follow-up results, and molecular spectrum of Chinese patients [ 5 , 6 , 8 , 9 ]. In this study, we report 26 cases of GDH-HI that were confirmed by genetic diagnosis.…”