Classification of GCK-MODY in a child with mild hyperglycemia and islet autoantibody positivity: a diagnostic challenge

Abstract

We report a 9-year-old female who presented with mild, persistent hyperglycemia, with hemoglobin A1c and oral glucose tolerance test results in the prediabetes range, relatively preserved C-peptide, and mildly positive glutamate decarboxylase 65 autoantibody levels. A strong family history of lean, noninsulin-dependent diabetes suggested a possible monogenic cause. Genetic testing with a 28-gene maturity-onset diabetes of the young (MODY) panel identified a heterozygous variant of uncertain significance in GCK (NM_000162.5:c.179C>T [p.Thr60Ile]). Following review by the ClinGen Monogenic Diabetes Variant Curation Expert Panel, the GCK variant was reclassified as pathogenic, confirming a diagnosis of glucokinase (GCK)-MODY/GCK-hyperglycemia, a stable form of mild hyperglycemia that does not require pharmacologic treatment. Subsequent genetic testing of the father confirmed paternal inheritance. Due to the presence of a positive islet autoantibody, she was counseled on the potential for autoimmune diabetes and advised to continue periodic monitoring. This case illustrates the diagnostic complexity of differentiating monogenic hyperglycemia from autoimmune diabetes in children.

Introduction

Maturity-onset diabetes of the young (MODY) refers to a group of monogenic diabetes types primarily caused by variants in genes regulating pancreatic β-cell function. Maturity-onset diabetes of the young is inherited in an autosomal dominant pattern and accounts for 1.1-6.5% of pediatric diabetes cases [1]. Among its various subtypes, the most prevalent form is glucokinase-MODY (GCK-MODY), resulting from pathogenic variants in the GCK gene. GCK encodes glucokinase, the principal β-cell glucose sensor, which controls the rate of glucose phosphorylation and subsequent insulin secretion [2]. Variants in GCK alter the blood glucose threshold required to trigger insulin release.

Differentiating MODY from more common diabetes types—namely type 1 diabetes (T1D) and type 2 diabetes (T2D)—is clinically important, as the recommended treatment, associated risks, and family testing considerations differ substantially. Individuals with GCK-MODY typically present with mild, nonprogressive fasting hyperglycemia from birth, rarely develop long-term complications, and usually do not require pharmacologic therapy. Because blood sugar is often in the prediabetic range with limited complications, GCK-MODY is sometimes denoted as GCK-hyperglycemia. By contrast, T1D involves progressive autoimmune destruction of pancreatic β cells, necessitating lifelong insulin therapy [3]. T1D accounts for greater than 80% of all pediatric diabetes cases [4]. Current diagnostic strategies utilize the presence of islet autoantibodies as biomarkers of β-cell destruction to differentiate T1D from monogenic and other diabetes types.

We report the case of a child with prediabetes, a positive islet autoantibody test, and a pathogenic GCK variant originally classified as a variant of uncertain significance (VUS). This co-occurrence underscores the diagnostic and clinical management challenges in distinguishing GCK-MODY from autoimmune diabetes in youth.

Case presentation

A 9-year-old female was evaluated for persistent hyperglycemia, discovered incidentally during workup for intermittent vomiting episodes of unclear etiology. One year prior, her hemoglobin A1c (HbA1c) was 5.8% (40 mmol/mol) (prediabetes range: 5.7-6.4% [39-46 mmol/mol]). Subsequent values ranged between 6.0 and 6.3% (42-45 mmol/mol), with her most recent reading at 5.8% (40 mmol/mol). Six months later, an oral glucose tolerance test revealed a fasting glucose of 98 mg/dL (5.44 mmol/L), within the normal range (≤100 mg/dL), and a 2-hour glucose of 157 mg/dL (8.68 mmol/L), consistent with prediabetes (140-199 mg/dL). The patient denied polyuria, polydipsia, and weight loss.

At the time of presentation, islet autoantibody testing revealed mildly positive glutamate decarboxylase 65 autoantibodies (GADAs) at 11 U/mL (reference range <5 U/mL), with insulin and islet antigen-2 autoantibodies (IA-2As) being negative. Nonfasting C-peptide was 2.9 ng/mL (0.96 nmol/L) with concurrent glucose of 128 mg/dL (7.1 mmol/L).

Her body mass index was at the 87th percentile for age and sex (overweight range: 85th to <95th percentile) at 3 years of age and progressively declined to the 27th percentile (normal range) at age 9. Height consistently tracked along the 50th percentile, within but at the lower end of her mid-parental target height. Physical examination was unremarkable, without overweight/obesity or acanthosis nigricans.

Family history was notable for nonobese, noninsulin-dependent diabetes in the father and paternal grandmother and T1D in 1 maternal cousin. Father was diagnosed with T2D in his early thirties and paternal grandmother as an adult; both were prescribed metformin, which proved ineffective in hyperglycemia control, leading both to discontinue therapy. The maternal cousin was diagnosed in childhood and exhibited typical T1D symptoms.

Diagnostic assessment

Given the strong paternal history of atypical diabetes, genetic testing was pursued to clarify the cause of hyperglycemia. A 28-gene MODY panel (Invitae) identified a heterozygous VUS in GCK(NM_000162.5:c.179C>T [p.Thr60Ile]) and MNX1(NM_005515.4:c.449G>A [p.Gly149Ser]). Consultation with the ClinGen Monogenic Diabetes Expert Panel Variant Curation Expert Panel (MDEP VCEP; https://www.clinicalgenome.org/affiliation/50016/) determined that the MNX1 variant was unlikely to explain the phenotype, as MNX1-related diabetes is autosomal recessive and presents with severe neonatal hyperglycemia.

Heterozygous GCK variants cause autosomal dominant GCK-MODY, a lifelong, stable, mild hyperglycemia consistent with the patient's presentation and family history. The heterozygous GCK VUS was subsequently reclassified as pathogenic (ClinVar Accession #SCV006304595.1) following MDEP's process of unpublished case solicitation from expert panelists, integration of published case data, biocuration using gene-specific guidelines, and expert consensus review.

The presence of a positive islet autoantibody raises the possibility of concurrent autoimmune diabetes. Whether GADA positivity reflects true islet autoimmunity and progressive β-cell loss remains uncertain and requires longitudinal follow-up.

Treatment

Consistent with GCK-MODY, no pharmacological therapy was initiated. Given the possibility of islet autoimmunity causing progressive loss of β-cell function, the family was counseled to monitor symptoms and check glucose levels at home weekly—both fasting and 2 hours after eating—but to monitor daily during illness or other stress.

Outcome and follow-up

The patient remains asymptomatic without polyuria, polydipsia, or weight loss. The family was advised to monitor C-peptide and HbA1c levels closely, with testing every 3 months, and to repeat autoantibody testing annually. Family testing for the identified GCK variant was advised to facilitate accurate diagnosis among relatives. The variant was found to be inherited from the affected father.

Discussion

This case illustrates the diagnostic complexity of distinguishing GCK-MODY and other MODY subtypes from autoimmune diabetes in a child with positive islet autoantibodies. Traditionally, the absence of islet autoantibodies with abnormal glycemic presentation is necessary before recommending MODY genetic testing. However, this approach can obscure underlying monogenic diabetes, particularly in atypical or mixed presentations [1]. The phenomenon of antibody-positive MODY, although rare, may reflect a coincidental finding or a concomitant diagnosis [1, 3]. Such challenges contribute to underdiagnosis or misclassification. Accurate identification of GCK-MODY has direct implications for clinical management, as treatment involves conservative measures such as dietary guidance and monitoring [3]. In contrast, T1D leads to insulin dependence, characterized by difficulty maintaining glucose control, weight loss, risk of diabetic ketoacidosis (DKA), and, in children, deceleration of linear growth.

Conventionally, the presence of islet autoantibodies—particularly GADA, IA-2A, and Zinc transporter 8—signals T1D onset. Although positivity for multiple autoantibodies is more common in pediatric T1D, 20% of children present with a single islet autoantibody [5]. Nonfasting C-peptide in this patient was 2.9 ng/mL (0.96 nmol/L), greater than the 95th percentile observed in children with new-onset T1D (mean 0.65 ng/mL, standard deviation 0.9 ng/mL) [6]. Pediatric T1D, unlike monogenic diabetes and T2D, is typically characterized by rapid β-cell loss and low C-peptide at diagnosis. However, this patient's monogenic diabetes and history of elevated HbA1c may have led to an earlier diagnosis in the autoimmune process of β-cell destruction, resulting in higher C-peptide level at presentation. This phenomenon is documented among individuals identified through systematic screening for islet autoimmunity [7].

Given the risk of islet autoimmunity and progressive β-cell loss, the family was counseled to monitor symptoms and perform weekly home glucose checks, both fasting and postprandial. Rising glucose levels would suggest declining β-cell function, consistent with autoimmune T1D. Early detection is essential to prevent chronic hyperglycemia and DKA, which carry both acute risk and adverse long-term outcomes.

However, the GADA result warrants cautious interpretation. Of the autoantibodies used clinically, GADA is the least specific for islet autoimmunity. Among initially diabetes-free relatives of patients with T1D, GADA positivity confers a lower risk of progression to multiple autoantibody positivity and clinical T1D than IA-2A or insulin autoantibodies [8]. High-affinity assays [9] and specific GADA epitopes [10] improve risk prediction but are not yet clinically available.

A UK study analyzing 508 plasma samples from individuals with MODY found islet autoantibodies in 5 cases—a prevalence comparable with control populations [11]. The authors concluded that autoantibody testing provides good discriminatory power between T1D and MODY, noting IA-2A positivity strongly indicates T1D and generally precludes further MODY genetic testing. Conversely, isolated GADA positivity may warrant additional evaluation, particularly in patients with nonprogressive hyperglycemia and preserved β-cell function [11]. In contrast, a Czech cohort study identified GADA positivity in 7 of 28 GCK-MODY cases and IA-2A positivity in 1 case [12]. Higher prevalence, including IA-2A positivity in a GCK-MODY patient, underscores variability in immunologic presentation across populations and highlights the need to interpret autoantibody results within the broader diagnostic context.

Importantly, GCK-MODY does not confer protection against other forms of diabetes when compared with other individuals in the population. Coexistence of T1D and GCK-MODY has been previously reported, supporting a dual-diagnosis model rather than misclassification in selected patients [13]. A recent pediatric case report described a patient with a pathogenic GCK variant who subsequently developed T1D with progressive β-cell loss, suggesting that monogenic glucose-sensing defects and autoimmune β-cell destruction can occur independently in the same individual [13].

Furthermore, recent population-level data challenge the traditional view of GCK-MODY as universally benign when another cause of diabetes coexists. A large retrospective study found that carriers of pathogenic GCK variants who develop T2D are at significant risk for secondary complications at rates similar to the general T2D population [14]. These findings underscore that although isolated GCK-MODY is typically benign, ongoing metabolic surveillance is important when additional risk factors or autoimmune markers are present. Our patient has GCK-MODY and a hereditary risk for slowly progressive insulin-dependent diabetes given her maternal cousin's diagnosis; however, her minimally positive GADA titer is associated with lower risk of progression to insulin dependence [15], supporting continued monitoring.

Clinical best practice evaluates the full clinical picture—glucose trends, C-peptide levels, autoantibody profiles, and family history—prior to initiating genetic testing [11, 12, 16]. Assessing multiple autoantibody profiles alongside serum markers reduces masking of MODY. In MODY cases, the likelihood of 2 positive autoantibody measurements with no concomitant autoimmune diagnosis is minuscule; therefore, genetic testing is discouraged in such instances [11]. In this patient, mildly elevated GADAs were present alongside negative IA-2A and insulin autoantibodies. Additionally, C-peptide remained within normal limits, suggesting preserved β-cell function. These findings argue against T1D and underscore the importance of interpreting autoantibody positivity alongside other biomarkers.

HbA1c levels in the prediabetic range, preserved C-peptide, and a strong paternal history of noninsulin-dependent diabetes all supported monogenic etiology. The identification of a GCK VUS introduced additional diagnostic ambiguity. Over 900 GCK variants are known, including missense, deletion, and insertion mutations that differentially affect clinical expression [17]. Given this diversity, accurate classification of pathogenic variants is critical for guiding management, particularly when treatment decisions depend on genetic etiology. Classification of pathogenic variants significantly improves diagnostic success following genetic testing, especially in MODY cases similar to our patient [18, 19].

Variant classification requires integration of population frequency data, in silico predictive tools, case-level evidence, cosegregation analysis, and in vitro data. In our patient, the GCK variant was classified as pathogenic by the MDEP VCEP, which applies rigorous, standardized criteria for variant interpretation. A prior published case report [10] and several unpublished occurrences in affected individuals supported this classification. As expected, given its pathogenic classification, the variant was paternally inherited. For variants with less evidence available, testing additional affected relatives—both those with noninsulin-dependent diabetes or mild hyperglycemia as well as those with proven euglycemia—can provide further segregation evidence to support pathogenicity [11, 12, 16, 18]. Although not required in this particular instance for variant classification, cascade testing of relatives is encouraged to guide their hyperglycemia management.

Variant of uncertain significance may later be reclassified as pathogenic or benign as new evidence emerges. Some of this evidence may already exist in unpublished data from global laboratories specializing in monogenic diabetes, which share case information with MDEP. Clinicians are therefore advised to contact MDEP upon receiving a VUS in a monogenic diabetes gene, particularly when the gene matches the patient's phenotype. Additionally, VUS classification should be reevaluated periodically, typically annually, to maintain diagnostic accuracy.

In conclusion, this case highlights the importance of a comprehensive, multifactorial approach in identifying the etiology of hyperglycemia. The presence of a positive islet autoantibody, particularly GADA, should not exclude monogenic diabetes without further investigation—especially when titers are low, β-cell function is preserved, and family history is suggestive. Continued refinement and integration of clinical, immunologic, and genetic tools will be essential to improving diagnostic accuracy and ensuring timely, cost-effective management of GCK-MODY and other MODY presentations.

Learning points

• Mild, stable hyperglycemia with preserved C-peptide, a strong family history of noninsulin-requiring diabetes or mild hyperglycemia, and absence of T2D risk factors in patient or affected family members should prompt consideration of monogenic diabetes, even with islet autoantibody positivity.

• Variants of uncertain significance may be reclassified as pathogenic evidence evolves, and expert curation enhances diagnostic accuracy.

• Recognizing GCK-MODY prevents unnecessary treatment, guides follow-up, and informs family testing.

Contributors

A.N.Y wrote the first draft of the manuscript. J.J.B. managed the patient's clinical care. A.N.Y., M.J.R., T.I.P., M.T., and J.J.B. interpreted the clinical and genetic data. C.O.J. led the curation and expert panel review for the variant identified in this patient. All authors edited, reviewed, and approved the final version for submission.

Funding

No public or commercial funding.

Disclosures

The authors declare that they have no known competing financial interest or personal relationship that could have appeared to influence the work reported in this paper.

Informed patient consent for publication

Signed informed consent obtained directly from the patient's relatives or guardians.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed.