Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism

Johnson, Stéphanie; Leo, Paul; McInerney-Leo, Aideen; Anderson, Lisa K.; Marshall, Mhairi; McGown, Ivan; Newell, Felicity; Brown, Matthew A.; Conwell, Louise S.; Harris, Max; Duncan, Emma L.

doi:10.1111/pedi.12638

Cited by 16 publications

(16 citation statements)

References 31 publications

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“…Supporting our use of ACMG criteria, we demonstrated enrichment of pathogenic/likely pathogenic variants and VUS in the overall diabetes population, and individually in the Ab− T1DM and T2DM populations, when compared to an unselected control population. Controls and cases were sequenced using different methodologies; however, coverage of MODY genes in both groups was comparable (data for control group shown in Reference). One previous study has specified their criteria for variant classification.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort

et al. 2018

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“…Despite diagnostic and therapeutic advances, HH remains an important cause of morbidity in children, still accounting for 26-44% of permanent intellectual disabilities, especially in neonatal-onset patients. The increasing use of NGS target panels, combined with clinical, biochemical and imaging findings allows differentiating the diagnostic management of children with F-CHH, surgically curable, from those with D-CHH, more conservatively treated with pharmacological and nutritional interventions [200].…”

Section: Developing the Hh Transition Pathwaysmentioning

confidence: 99%

Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management

Güemes

Rahman

Kapoor

et al. 2020

Rev Endocr Metab Disord

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Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.

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“…Exome sequencing, pipeline processing, quality control and variant curation was performed as previously described 13 (detailed in Supplementary Appendix: Methods). Exome data from the proband was analysed for good-quality likely damaging rare variants in known MODY genes 1 , using a conservative minor allele frequency (MAF) threshold of <0.001, based on: (a) prevalence of paediatric diabetes of 0.2% 14 ; and (b) prevalence of MODY mutations in 2% of a pediatric diabetes population 2 ; further, most MODY mutations are private.…”

Section: Exome Sequencingmentioning

confidence: 99%

“…Maturity-onset diabetes of the young (MODY) is a rare monogenic cause of familial diabetes. To date, 13 MODY genes have been confirmed, all involved in pancreatic β-cell insulin secretion and all with autosomal dominant transmission 1 . 2-2.5% of pediatric diabetes cases carry pathogenic/likely pathogenic variants in MODY genes 2,3 ; however, MODY is often undiagnosed, either because the diagnosis is not considered 4 or because genetic screening is limited.…”

Section: Introductionmentioning

confidence: 99%

A novel mutation inKCNK16causing a gain-of-function in the TALK-1 potassium channel: a new cause of maturity onset diabetes of the young

Graff

Johnson

Leo

et al. 2020

Preprint

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Word count2820 3 ABSTRACT Background Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired glucose-stimulated insulin secretion (GSIS). Mechanisms include β-cell KATP channel dysfunction (e.g., KCNJ11 (MODY13) or ABCC8 (MODY12) mutations); however, no other β-cell channelopathies have been identified in MODY. MethodsA four-generation family with autosomal dominant non-obese, non-ketotic antibody-negative diabetes, without mutations in known MODY genes, underwent exome sequencing. Whole-cell and single-channel K + currents, Ca 2+ handling, and GSIS were determined in cells expressing either mutated or wild-type (WT) protein. ResultsWe identified a novel non-synonymous genetic mutation in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and -cell-restricted K + channel transcript and encodes the two-pore-domain K + channel TALK-1. Whole-cell K + currents in transfected HEK293 cells demonstrated drastic (312-fold increase) gain-of-function with TALK-1 Leu144Pro vs. WT, due to greater single channel activity. Glucose-stimulated cytosolic Ca 2+ influx was inhibited in mouse islets expressing TALK-1 Leu114Pro (area under the curve [AUC] at 20mM glucose: Leu114Pro 60.1 vs. WT 89.1; P=0.030) and less endoplasmic reticulum calcium storage (cyclopiazonic acid-induced release AUC:Leu114Pro 17.5 vs. WT 46.8; P=0.008). TALK-1 Leu114Pro significantly blunted GSIS compared to TALK-1 WT in both mouse (52% decrease, P=0.039) and human (38% decrease, P=0.019) islets.

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Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism

Abstract: WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection.

Cited by 16 publications

References 31 publications

Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort

Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort

Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management

A novel mutation inKCNK16causing a gain-of-function in the TALK-1 potassium channel: a new cause of maturity onset diabetes of the young

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