Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

Breidbart, Emily; Deng, Liyong; Lanzano, Patricia; Fan, Xiao; Jiang, Guo Liang; Leibel, Rudolph L.; LeDuc, Charles A.; Chung, Wendy K.

doi:10.1515/jpem-2020-0501

Cited by 14 publications

(8 citation statements)

References 36 publications

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“…Limiting to the P/LP variants, GCK-MODY was the most common, followed by HNF1A-, HNF4A-and HNF1B-MODY (Figure 2). This is in line with the recent large-scale studies 21,[34][35][36] , and is not surprising considering the high population prevalence (estimated at 1.1 in 1000) of deleterious GCK variants in the general population 32 . When mildly hyperglycemic patients are included as in pediatric studies, GCK variants are likely to be the most common, whereas HNF1A variants tend to be more common in studies leaning toward symptomatic patients 37 .…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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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“…Diabetes mellitus prevailed in 60% of the patients' families. Aside from blood glucose, there were no signi cant differences in MODY13 patients' sex, ethnicity, blood pressure, C-peptide, FT4, or insulin-related antibodies when versus KCNJ11 mutation-associated neonatal diabetes mellitus 16,[23][24][25] .…”

Section: Discussionmentioning

confidence: 86%

A synonymous variant in KCNJ11 leading to MODY13: a case report and literature review

Chen

Piao

Sang

2023

Preprint

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137words Background: MODY13 (Maturity-onset diabetes of the young, type 13) is monogenic diabetes associated with the KCNJ11 mutation rarely reported to date. A patient with c.843C>T(p.L281=) in the KCNJ11 gene is reported only in a Chinese patient with congenital hyperinsulinemia. There is no patient diagnosed with MODY13 carrying a synonymous heterozygous variant in the KCNJ11 reported till now. Method: We followed a 9-year-old boy presenting ketosis and diagnosed with MODY13. Whole-exome sequencing (WES) and Sanger validation were performed on the proband and his parents, respectively. Then bioinformatics software was used to predict the RNA structure and protein function. Result: The clinical characteristics and genetic traits of a 9-year-old boy with MODY13 are described in this study. WES revealed the synonymous heterozygous variant c.843C>T (p.L281=) in the KCNJ11 exon 1 in this patient, which prompted the opposite phenotype previously described. The patient and his mother who carries c.843C>T have morphologically comparable RNA structures of KCNJ11 which is completely separated from his mother. Conclusion: A c.843C>T (p.L281=) variant in the KCNJ11 gene contributes to MODY13. In clinical practice, WES should be applied to diagnose hyperglycemia in patients without characteristic clinical symptoms of diabetes to improve prognosis.

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“…While MODY patients were described as nonobese until a few years ago, more recent studies have shown that a relevant proportion of patients with monogenic diabetes are significantly overweight or obese [ 42 , 44 ]. While T2D manifestation in normal-weight children and adolescents is almost excluded, the presence of obesity does not make it possible to clearly define T2D in this patient group [ 45 , 46 ]. All genetically screened patients showed an insulin secretion disorder during the OGTT.…”

Section: Discussionmentioning

confidence: 99%

Insulin Secretion Defect in Children and Adolescents with Obesity: Clinical and Molecular Genetic Characterization

Enders-Seidlitz,

Raile,

Gong

et al. 2024

Journal of Diabetes Research

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Introduction. Childhood obesity is increasing worldwide and presents as a global health issue due to multiple metabolic comorbidities. About 1% of adolescents with obesity develop type 2 diabetes (T2D); however, little is known about the genetic and pathophysiological background at young age. The objective of this study was to assess the prevalence of impaired glucose regulation (IGR) in a large cohort of children and adolescents with obesity and to characterize insulin sensitivity and insulin secretion. We also wanted to investigate adolescents with insulin secretion disorder more closely and analyze possible candidate genes of diabetes in a subcohort. Methods. We included children and adolescents with obesity who completed an oral glucose tolerance test (OGTT, glucose+insulin) in the outpatient clinic. We calculated Matsuda index, the area under the curve (AUC (Ins/Glu)), and an oral disposition index (ISSI-2) to estimate insulin resistance and beta-cell function. We identified patients with IGR and low insulin secretion (maximum insulin during OGTT<200 mU/l) and tested a subgroup using next generation sequencing to identify possible mutations in 103 candidate genes. Results. The total group consisted of 903 children and adolescents with obesity. 4.5% showed impaired fasting glucose, 9.4% impaired glucose tolerance, and 1.2% T2D. Matsuda index and Total AUC (Ins/Glu) showed a hyperbolic relationship. Out of 39 patients with low insulin secretion, we performed genetic testing on 12 patients. We found five monogenetic defects (ABCC8 (n=3), GCK (n=1), and GLI2/PTF1A (n=1)). Conclusion. Using surrogate parameters of beta-cell function and insulin resistance can help identify patients with insulin secretion disorder. A prevalence of 40% mutations of known diabetes genes in the subgroup with low insulin secretion suggests that at least 1.7% of patients with adolescent obesity have monogenic diabetes. A successful molecular genetic diagnosis can help to improve individual therapy.

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Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

Cited by 14 publications

References 36 publications

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

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

A synonymous variant in KCNJ11 leading to MODY13: a case report and literature review

Insulin Secretion Defect in Children and Adolescents with Obesity: Clinical and Molecular Genetic Characterization

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