NGS Analysis Revealed Digenic Heterozygous GCK and HNF1A Variants in a Child with Mild Hyperglycemia: A Case Report

Abstract

Monogenic diabetes (MD) represents a heterogeneous group of disorders whose most frequent form is maturity-onset diabetes of the young (MODY). MD is predominantly caused by a mutation in a single gene. We report a case of a female patient with suspected MD and a positive family history for diabetes and obesity. In this patient, two gene variants have been identified by next-generation sequencing (NGS): one in the Glucokinase (GCK) gene reported in the Human Gene Mutation Database (HGMD) and in the literature associated with GCK/MODY, and the other in the hepatocyte nuclear factor 1A (HNF1A) gene not previously described. The GCK variant was also identified in the hyperglycemic father, whereas the HNF1A variant was present in the mother. This new case of digenic GCK/HNF1A variants identified in a hyperglycemic subject, evidences the importance of NGS analysis in patients with suspected MD. In fact, this methodology will allow us to both increase the number of diagnoses and to identify mutations in more than one gene, with a better understanding of the genetic cause, and the clinical course, of the disease.

An accurate prediction model of digenic interaction for estimating pathogenic gene pairs of human diseases

“…Furthermore, Iafusco et al reported a new case of digenic GCK/HNF1A variants (DIEP predicted probability = 0.946) identified in a hyperglycemic subject. They indicated that identifying mutations in more than one gene will help researchers better understand the genetic cause of the diseases [78] . Therefore, despite the limited number of digenic pairs, DIEP did provide more reliable predicting results with a better performance.…”

Digenic variant interpretation with hypothesis-driven explainable AI

“…To collect data for training purposes, we curated a dataset of pathogenic digenic combinations extracted both from DIDA 26 , from literature review [29][30][31][32] and from an internal unpublished database. Variants have been reported with their genomic coordinates and associated with the caused phenotypes expressed as Human Phenotype Ontology (HPO) terms 33 , if explicitly available.…”

The Pathogenic Diagnosis in Pediatric Diabetology: Next Generation Sequencing and Precision Therapy

“…As in many other fields of medicine, such as MD, NGS techniques have become the cornerstone of precision diagnosis. We have moved from the need to test gene by gene by Sanger sequencing on the bases of clinical suspicion and clinical phenotype to the possibility of performing multigene panel analyses, allowing us to diagnose rare monogenic diabetes subtypes previously underdiagnosed or even undiagnosed [ 5 , 6 , 7 ]. The multigenic approach is proving to be very practical and capable of providing results, often disengaging from clinical diagnosis.…”

“…The multigenic approach is proving to be very practical and capable of providing results, often disengaging from clinical diagnosis. Furthermore, this methodology may also allow to identify digenic mutations that would otherwise remain undetected in a monogenic approach [ 7 , 8 ].…”