Molecular genetics and phenotype of 26 Vietnamese patients with congenital hyperinsulinism

Dũng, Vũ Chí; Liêm, Nguyễn Thanh; Thảo, Bùi Phương; Khánh, Nguyễn Ngọc; Ngọc, Cấn Thị Bích; Hoan, Nguyen Thi; Dung, Khu Thi Khanh; Nhu, Le To; Duong, Dang Anh; Dat, Nguyen Phu; Flanagan, Sarah P.; Ellard, Sian

doi:10.1186/1687-9856-2013-s1-p179

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“…Interestingly, of the previously reported K ATP channel variants, four are listed in association with hyperinsulinemic hypoglycemia in the HGMD database. Described clinical phenotypes of patients with these variants (p.Arg1486Lys 38 , p.Gly1378Ser 39 , p.Asp1030Asn 40 , p.Arg1420His 33 ) are compatible with the diagnosis of congenital hyperinsulinism, and for p.Gly1378Ser and p.Arg1420His, in vitro evidence of the loss of function has been reported 41,42 . These findings could simply be the incidental identification of asymptomatic carriers of loss‐of‐function, hyperinsulinemic variants not related to diabetes.…”

Section: Discussionmentioning

confidence: 96%

Targeted gene panel analysis of Japanese patients with maturity‐onset diabetes of the young‐like diabetes mellitus: Roles of inactivating variants in the ABCC8 and insulin resistance genes

Yorifuji

Watanabe

Kitayama

et al. 2022

J of Diabetes Invest

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Aims/Introduction: To investigate the genetic background of Japanese patients with suspected maturity-onset diabetes of the young (MODY). Materials and Methods: On 340 proband patients referred from across Japan, genomic variants were analyzed using a targeted multigene panel analysis combined with the multiplex ligation probe amplification (MLPA) analysis, mitochondrial m.3243A > G analysis and methylation-specific polymerase chain reaction of the imprinted 6q24 locus. Pathogenic/likely pathogenic variants were listed according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Additionally, variants with a population frequency <0.001 and Combined Annotation Dependent Depletion score >20 (CS >20) were listed as rare variants of uncertain significance-CS >20. Results: A total of 157 pathogenic/likely pathogenic variants and 44 rare variants of uncertain significance-CS >20 were identified. In the pathogenic/likely pathogenic variants, alterations in the GCK gene were the most common (82, 52.2%) followed by HNF1A (29, 18.5%), HNF4A (13, 8.3%) and HNF1B (13, 8.3%). One patient was a 29.5% mosaic with a truncating INSR variant. In the rare variants of uncertain significance-CS >20, 20 (45.5%) were in the genes coding for the adenosine triphosphate-sensitive potassium channel, KCNJ11 or ABCC8, and four were in the genes of the insulin-signaling pathway, INSR and PIK3R1. Four variants in ABCC8 were previously reported in patients with congenital hyperinsulinism, suggesting the inactivating nature of these variants, and at least two of our patients had a history of congenital hyperinsulinism evolving into diabetes. In two patients with INSR or PIK3R1 variants, insulin resistance was evident at diagnosis. Conclusions: Causative genomic variants could be identified in at least 46.2% of clinically suspected MODY patients. ABCC8-MODY with inactivating variants could represent a distinct category of MODY. Genes of insulin resistance should be included in the sequencing panel for MODY.

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