Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism

Emanuela Ponzi, Arianna Maiorana, Francesca Romana Lepri, Mafalda Mucciolo, Michela Semeraro, Roberta Taurisano, Giorgia Olivieri, Antonio Novelli, Carlo Dionisi-Vici

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Abstract

OBJECTIVES: To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia.

STUDY DESIGN: Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders. Molecular data were compared with clinical and biochemical data.

RESULTS: A proven diagnosis was obtained in 78% of patients with suspicion for a single candidate gene, in 49% with multiple candidate genes, and in 33% with no candidate gene. The diagnostic yield was 48% for hyperinsulinemic hypoglycemia, 66% per fatty acid-oxidation and ketogenesis defects, 59% for glycogen storage diseases and other carbohydrate disorders, and 67% for mitochondrial disorders.

CONCLUSIONS: This approach provided a diagnosis in ~50% of patients in whom clinical and laboratory evaluation did not allow identification of a single candidate gene and a diagnosis was established in 33% of patients belonging to the no candidate gene class. Next generation sequencing technique is cost-effective compared with Sanger sequencing of multiple genes and represents a powerful tool for the diagnosis of inborn errors of metabolism presenting with persistent hypoglycemia.

Original languageEnglish
Pages (from-to)272-278.e4
Number of pages7
JournalJournal of Pediatrics
Volume202
DOIs
Publication statusPublished - Nov 2018

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Inborn Errors Metabolism
Hypoglycemia
Genes
Glycogen Storage Disease
Mitochondrial Diseases
Fatty Acids
Carbohydrate Metabolism
Carbohydrates

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Persistent Hypoglycemia in Children : Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism. / Ponzi, Emanuela; Maiorana, Arianna; Lepri, Francesca Romana; Mucciolo, Mafalda; Semeraro, Michela; Taurisano, Roberta; Olivieri, Giorgia; Novelli, Antonio; Dionisi-Vici, Carlo.

In: Journal of Pediatrics, Vol. 202, 11.2018, p. 272-278.e4.

Research output: Contribution to journalArticle

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abstract = "OBJECTIVES: To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia.STUDY DESIGN: Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders. Molecular data were compared with clinical and biochemical data.RESULTS: A proven diagnosis was obtained in 78{\%} of patients with suspicion for a single candidate gene, in 49{\%} with multiple candidate genes, and in 33{\%} with no candidate gene. The diagnostic yield was 48{\%} for hyperinsulinemic hypoglycemia, 66{\%} per fatty acid-oxidation and ketogenesis defects, 59{\%} for glycogen storage diseases and other carbohydrate disorders, and 67{\%} for mitochondrial disorders.CONCLUSIONS: This approach provided a diagnosis in ~50{\%} of patients in whom clinical and laboratory evaluation did not allow identification of a single candidate gene and a diagnosis was established in 33{\%} of patients belonging to the no candidate gene class. Next generation sequencing technique is cost-effective compared with Sanger sequencing of multiple genes and represents a powerful tool for the diagnosis of inborn errors of metabolism presenting with persistent hypoglycemia.",
author = "Emanuela Ponzi and Arianna Maiorana and Lepri, {Francesca Romana} and Mafalda Mucciolo and Michela Semeraro and Roberta Taurisano and Giorgia Olivieri and Antonio Novelli and Carlo Dionisi-Vici",
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T2 - Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism

AU - Ponzi, Emanuela

AU - Maiorana, Arianna

AU - Lepri, Francesca Romana

AU - Mucciolo, Mafalda

AU - Semeraro, Michela

AU - Taurisano, Roberta

AU - Olivieri, Giorgia

AU - Novelli, Antonio

AU - Dionisi-Vici, Carlo

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/11

Y1 - 2018/11

N2 - OBJECTIVES: To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia.STUDY DESIGN: Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders. Molecular data were compared with clinical and biochemical data.RESULTS: A proven diagnosis was obtained in 78% of patients with suspicion for a single candidate gene, in 49% with multiple candidate genes, and in 33% with no candidate gene. The diagnostic yield was 48% for hyperinsulinemic hypoglycemia, 66% per fatty acid-oxidation and ketogenesis defects, 59% for glycogen storage diseases and other carbohydrate disorders, and 67% for mitochondrial disorders.CONCLUSIONS: This approach provided a diagnosis in ~50% of patients in whom clinical and laboratory evaluation did not allow identification of a single candidate gene and a diagnosis was established in 33% of patients belonging to the no candidate gene class. Next generation sequencing technique is cost-effective compared with Sanger sequencing of multiple genes and represents a powerful tool for the diagnosis of inborn errors of metabolism presenting with persistent hypoglycemia.

AB - OBJECTIVES: To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia.STUDY DESIGN: Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders. Molecular data were compared with clinical and biochemical data.RESULTS: A proven diagnosis was obtained in 78% of patients with suspicion for a single candidate gene, in 49% with multiple candidate genes, and in 33% with no candidate gene. The diagnostic yield was 48% for hyperinsulinemic hypoglycemia, 66% per fatty acid-oxidation and ketogenesis defects, 59% for glycogen storage diseases and other carbohydrate disorders, and 67% for mitochondrial disorders.CONCLUSIONS: This approach provided a diagnosis in ~50% of patients in whom clinical and laboratory evaluation did not allow identification of a single candidate gene and a diagnosis was established in 33% of patients belonging to the no candidate gene class. Next generation sequencing technique is cost-effective compared with Sanger sequencing of multiple genes and represents a powerful tool for the diagnosis of inborn errors of metabolism presenting with persistent hypoglycemia.

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DO - 10.1016/j.jpeds.2018.06.050

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JO - Journal of Pediatrics

JF - Journal of Pediatrics

SN - 0022-3476

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