Exome sequencing revealed DNA variants in NCOR1, IGF2BP1, SGLT2 and NEK11 as potential novel causes of ketotic hypoglycemia in children

Yazeid Alhaidan,Anders Jørgen Schou,Martin J Larsen,Henrik Thybo Christesen,Klaus Brusgaard,Maria H Stenlid,Mohammed A Al Balwi

doi:10.1038/s41598-020-58845-3

Abstract

Unexplained or idiopathic ketotic hypoglycemia (KH) is the most common type of hypoglycemia in children. The diagnosis is based on the exclusion of routine hormonal and metabolic causes of hypoglycemia. We aimed to identify novel genes that cause KH, as this may lead to a more targeted treatment. Deep phenotyping of ten preschool age at onset KH patients (boys, n = 5; girls, n = 5) was performed followed by trio exome sequencing and comprehensive bioinformatics analysis. Data analysis revealed four novel candidate genes: (1) NCOR1 in a patient with KH, iron deficiency and loose stools; (2) IGF2BP1 in a proband with KH, short stature and delayed bone age; (3) SLC5A2 in a proband with KH, intermittent glucosuria and extremely elevated p-GLP-1; and (4) NEK11 in a proband with ketotic hypoglycemia and liver affliction. These genes are associated with different metabolic processes, such as gluconeogenesis, translational regulation, and glucose transport. In conclusion, WES identified DNA variants in four different genes as potential novel causes of IKH, suggesting that IKH is a heterogeneous disorder that can be split into several novel diseases: NCOR1-KH, IGF2BP1-KH, SGLT2-KH or familial renal glucosuria KH, and NEK11-KH. Precision medicine treatment based on exome sequencing may lead to advances in the management of IKH.

Highlights

Hypoglycemia is the most common metabolic disease beyond infancy
Emergency departments showed an incidence of 3.9–4.0/100,000 admissions due to IKH11,15, the estimated prevalence of the different genetic disorders leading to hypoglycemia may vary considerably between populations and according to subtypes
A nonsyndromic, normal-weight Caucasian girl presented with p-glucose of 1.8 mmol/L and blood ketones 4.9 mmol/L at 22 months of age during an infection episode (HH16, Table 1)

Summary

Introduction

Hypoglycemia is the most common metabolic disease beyond infancy. Despite its frequency, the definition of hypoglycemia has been discussed for decades, and hypoglycemia “remains one of the most confused and contentious issues”, as stated by Cornblath et al.[1]. Hyperketotic hypoglycemia (KH) can occur in nondiabetic infants and children as a result of growth hormone deficiency, adrenal insufficiency, or disorders of glucose metabolism with intact fatty acid oxidation, including glycogen storage disease (GSD) type 0 [OMIM: 240600], III [OMIM: 232400], VI [OMIM: 232700] and IX [OMIM: 306000-261750-613027]3–9. Excluding such diagnoses, ketotic hypoglycemia after prolonged fasting in younger children has been categorized as idiopathic ketotic hypoglycemia (IKH) or accelerated starvation[10,11,12]. We investigate nine families with proposed IKH, applying a multistep screening strategy based on trio exome sequencing, to potentially identify a cause of IKH and improve treatment within the conceptual frame of personalized medicine

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Conclusion