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Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism.
J Pediatr 2018; 202:272-278.e4JPed

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.

Authors+Show Affiliations

Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Rome, Italy.Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Rome, Italy.Medical Genetics Unit, Medical Genetics Laboratory, Bambino Gesù Children's Hospital, Rome, Italy.Medical Genetics Unit, Medical Genetics Laboratory, Bambino Gesù Children's Hospital, Rome, Italy.Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Rome, Italy.Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Rome, Italy.Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Rome, Italy; Unit of Child Neurology, Catholic University, Fondazione Policlinico A. Gemelli, Rome, Italy.Medical Genetics Unit, Medical Genetics Laboratory, Bambino Gesù Children's Hospital, Rome, Italy.Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Rome, Italy. Electronic address: carlo.dionisivici@opbg.net.

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

30193751

Citation

Ponzi, Emanuela, et al. "Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism." The Journal of Pediatrics, vol. 202, 2018, pp. 272-278.e4.
Ponzi E, Maiorana A, Lepri FR, et al. Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism. J Pediatr. 2018;202:272-278.e4.
Ponzi, E., Maiorana, A., Lepri, F. R., Mucciolo, M., Semeraro, M., Taurisano, R., ... Dionisi-Vici, C. (2018). Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism. The Journal of Pediatrics, 202, pp. 272-278.e4. doi:10.1016/j.jpeds.2018.06.050.
Ponzi E, et al. Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism. J Pediatr. 2018;202:272-278.e4. PubMed PMID: 30193751.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Persistent Hypoglycemia in Children: 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, Y1 - 2018/09/05/ PY - 2017/12/19/received PY - 2018/05/26/revised PY - 2018/06/14/accepted PY - 2018/9/9/pubmed PY - 2019/3/5/medline PY - 2018/9/9/entrez KW - NGS KW - genetic diagnosis KW - glucose homeostasis KW - metabolic disorders SP - 272 EP - 278.e4 JF - The Journal of pediatrics JO - J. Pediatr. VL - 202 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. SN - 1097-6833 UR - https://www.unboundmedicine.com/medline/citation/30193751/Persistent_Hypoglycemia_in_Children:_Targeted_Gene_Panel_Improves_the_Diagnosis_of_Hypoglycemia_Due_to_Inborn_Errors_of_Metabolism L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3476(18)30875-8 DB - PRIME DP - Unbound Medicine ER -