Uncovering the molecular pathogenesis of congenital hyperinsulinism by panel gene sequencing in 32 Chinese patients

Abstract

Congenital hyperinsulinism (CHI) has been mostly associated with mutations in seven major genes. We retrospectively reviewed a cohort of 32 patients with CHI. Extensive mutational analysis (ABCC8,KCNJ11,GCK,GLUD1,HADH,HNF4A, and UCP2) was performed on Ion torrent platform, which could analyze hundreds of genes simultaneously with ultrahigh‐multiplex PCR using up to 6144 primer pairs in a single primer pool and address time‐sensitive samples with single‐day assays, from samples to annotated variants, to identify the genetic etiology of this disease. Thirty‐seven sequence changes were identified, including in ABCC8/KCNJ11 (n = 25, 65.7%), GCK (n = 2), HNF4A (n = 3), GLUD1 (n = 2), HADH (n = 4), and UCP2 (n = 1); these mutations included 14 disease‐causing mutations, eight rare SNPs, 14 common SNPs, and one novel mutation. Mutations were identified in 21 of 32 patients (65.6%). Among the patients with an identified mutation, 14 had mutations in ABCC8, one of which was combined with a GLUD1 mutation. Four patients had mutations in KCNJ11, 1 had a GCK mutation, 1 had a mutation in HADH, and two had a mutation in HNF4A. Among the 32 patients, the age at the onset of hyperinsulinemia ranged from the neonatal period to 1 year of age; five patients underwent a pancreatectomy due to intractable hyperinsulinemia. This study describes novel and previously identified mutations in patients with CHI. The spectrum of mutations in CHI patients represents an important tool for the diagnosis and prognosis of CHI patients in the Chinese population as well as for the genetic counseling of CHI families.

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).…”

“…These findings indicate that a geographical distribution difference exists in the mutational spectrum of the ABCC8 gene in the Chinese population. This mutation causes a frameshift and introduces a premature stop codon 75 codons downstream of the mutation, leading to the loss of the functional domain NBD2 (20).…”

Genotype and phenotype analysis of a cohort of patients with congenital hyperinsulinism based on DOPA-PET CT scanning

“…Genetic analysis of CHI-related genes could be informative, for example, paternal germline mutations in ABCC8 or KCNJ11 are associated with the focal form of CHI whereas biallelic recessive mutations are associated with the diffuse form [3, 11]. However, no CHI-related mutations can be found in about 50% of all cases worldwide [4, 15, 21, 23, 28]. Recently, an accurate and sensitive technique, positron emission tomography (PET) using fluorine-18-labeled L-dihydroxyphenylalanine ( 18 F-DOPA), has been applied in CHI to help with pre-operative localization of the focal lesion, but mainly in Caucasian populations [12, 20, 22].…”