Edited by: Andrea Mario Bolla, AUSL Piacenza, Italy
Reviewed by: Elif Ozsu, Ankara University Medical School, Türkiye
Arun Pandey, LEDTC Clinic, India
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Maturity-Onset Diabetes of the Young (MODY) comprises monogenic, non-syndromic forms of diabetes inherited in an autosomal dominant pattern. MODY is frequently misdiagnosed as type 1 diabetes (T1D), type 2 diabetes (T2D), or gestational diabetes mellitus (GDM). Studies suggest that 50–90% of MODY cases are erroneously classified as type 1 or type 2 diabetes, and up to 5% of women with GDM may have undiagnosed MODY. However, data regarding the clinical presentation and genetic characterization of MODY in Latin American populations remain scarce. This study aimed to describe the clinical, analytical, and genetic characteristics of MODY patients initially misdiagnosed as T1D, T2D, or GDM in a Latin American tertiary care center.
Medical history, clinical and laboratory data were obtained from electronic medical records to assess diagnostic accuracy and identify phenotypic patterns suggestive of MODY. Whole exome sequencing (WES) was employed to detect mutations related to monogenic variants.
We identified five patients with MODY. The median age at diabetes diagnosis was 13.6 years, while the median age at MODY diagnosis was 25.8 years. The average duration between the initial diabetes diagnosis and confirmation of MODY was 12.2 years. None of the patients presented with diabetic ketoacidosis at the onset of diabetes. All patients tested negative for islet cell autoimmunity. Of the five patients, two were initially misclassified as having T1D, two as T2D, and one as GDM. Whole-exome sequencing (WES) identified a pathogenic missense variant, c.94G>A (p.Gly32Ser), in the
MODY is often misdiagnosed, leading to delays in appropriate management. Whole-exome sequencing is crucial for identifying pathogenic variants, enabling accurate reclassification and tailored therapy.
Diabetes Mellitus (DM) is an increasingly prevalent and heterogeneous chronic disease comprising clusters of phenotypically distinct forms (
However, in the spectrum of DM, there exist atypical forms that do not align neatly with the traditional classifications of type 1 or type 2 diabetes (
MODY accounts for approximately 0.5–5% of all diabetes diagnoses and around 3.5% of those occurring before the age of 30 (
Misclassification of MODY is common due to its overlapping clinical features with both type 1 diabetes (T1D)—such as early onset and low body mass index—and type 2 diabetes (T2D), including preserved β-cell function and a positive family history. The broad clinical spectrum of MODY, combined with the absence of clear genotype–phenotype correlations—particularly in rare or low-penetrance subtypes—further complicates accurate diagnosis (
In this study, we present the clinical, biochemical, and genetic profiles of patients with MODY who were initially misdiagnosed as having T1D, T2D, or GDM in a Latin American tertiary care center. We also highlight the value of whole-exome sequencing (WES) as a tool for improving diagnostic accuracy and guiding personalized therapy in monogenic diabetes.
Medical history, clinical and laboratory data were obtained from electronic medical records to assess diagnostic accuracy and identify phenotypic patterns suggestive of MODY. The whole exome sequencing (WES) was used to detect mutations related to monogenic variants.
Clinical and genetic characteristics of the cases in
Clinical and genetic characteristics of MODY cases (
| Sex | Male | Female | Female | Male | Male | |
| Family history of diabetes | Mother and grandmother | Father and grandmother | Mother, aunts, cousins, and grandmother | Mother, brother, grandfather | Father | |
| Age of clinical diagnosis (years) | 9 | 19 | 19 | 13 | 8 | |
| Ketoacidosis | No | No | No | No | No | |
| Initial diagnosis | T1D | T2D | GDM | T2D | T1D | |
| Exeter Mody calculator | 8.20% | 12.60% | 12.60% | 75.50% | Cannot be calculated | |
| Age at the diagnostic of Mody (years) | 22 | 27 | 45 | 18 | 17 | |
| Years of diagnostic delay | 13 | 8 | 26 | 5 | 9 | |
| At diagnosis | Fasting glucose | 91.9 mg/dL | 93 mg/dL | 107 mg/dL | 130 mg/dL | 472 mg/dL |
| Fasting C-peptide | 0.78 ng/mL | 0.07 ng/mL | 0.18 ng/mL | 1 ng/mL | 0.64 ng/mL | |
| HbA1c | 6.6% | 7.97% | 6.85% | 6.28% | 18.66% | |
| CK-EPI | 119 ml/min/1.73 m2 | 131.71 ml/min/1.73 m2 | 113.59 ml/min/1.73 m2 | 127.67 ml/min/1.73 m2 | 188 ml/min/1.73 m2 | |
| Proteinuria | 106.79 mg/24 h | Test was not taken | 60.68 mg/24 h | 77.28 mg/24 h | 2,902 mg/24 h | |
| Autoantibodies (GAD65, IA2) | Negative | Negative | Negative | Negative | Negative | |
| Initial therapy | Insulin 0.5 IU/kg/day | Insulin 0.42 IU/kg/day | Insulin 0.73 IU/kg/day | None | Insulin | |
| Genotype | Gen | |||||
| Nucleotide change | c.709A>G | c.4135C>T | c.616dupC | c.613G>T | c.94G>A | |
| Aminoacid | p.Asn237Asp | p.Arg1379Cys | p.His206Profs*38 | p.Asp205Tyr | p.Gly32Ser | |
| Acmg Classification | Pathogenic | Pathogenic | Pathogenic | Likely pathogenic | Pathogenic | |
| Segregation | No tested | Son | No tested | Mother, brother, grandfather | ||
| At last follow-up | Fasting glucose | 76 mg/dL | 110 mg/dL | 176 mg/dL | 110 mg/dL | 114 mg/dL |
| HbA1c | 6.78% | 6% | 8.46% | 6.77% | 8.63% | |
| CK-EPI | 121.6 ml/min/1.73 m2 | 126.89 ml/min/1.73 m2 | 109.67 ml/min/1.73 m2 | 104.58 ml/min/1.73 m2 | 88.02 ml/min/1.73 m2 | |
| Current therapy | Glibenclamide 5 mg once daily + Insulin glargine + lixisenatide 16 IU/8 μg once daily | Glimepiride 4 mg daily | No change | None | Insulin glargine + regular insulin 1 IU/kg/day + empagliflozin 25 mg daily | |
A 23-year-old male South-American Ecuadorian patient attended a consultation in 2022. He had no apparent maternal-fetal complications but had a positive family history of presumed type 2 diabetes in his mother and grandmother. The patient presented with hyperglycemia of 466 mg/dL without ketoacidosis at the age of 9 years and was initially diagnosed with type 1 diabetes (T1D). On physical examination his weight at admission was 64 kg, but it gradually increased to 78.7 kg, reaching a body mass index (BMI) of 29 kg/m2. He was treated with a low-dose insulin regimen, consisting of basal insulin glargine at bedtime and prandial insulin glulisine, titrated to a total daily dose (TDD) of 0.5 IU/kg/day. This regimen achieved optimal metabolic control, with hemoglobin A1c of 6.6%. However, several factors raised doubts about the T1D diagnosis. In addition to his relatively low insulin requirements and absence of ketoacidosis, his fasting C-peptide levels remained at the lower limit of normal at 0.78 ng/mL even after 13 years of disease progression. Furthermore, his glutamic acid decarboxylase (GAD) and tyrosine phosphatase islet antigen-2 autoantibodies were negative. Although the patient's MODY probability calculator score was 8.2%, genetic panel sequencing for monogenic diabetes was performed. The results identified a pathogenic missense variant, c.709A>G (p.Asn237Asp), in the
A 27-year-old female South-American Ecuadorian presented to our diabetes clinic with a history of type 2 diabetes, first diagnosed at age 19, with a blood glucose level of 350 mg/dL, hypertriglyceridemia of 1,000 mg/dL (0–150 mg/dL), and no ketoacidosis. Her family history was notable for diabetes in her father and paternal grandmother. Additionally, 2 years ago, she had a child who was diagnosed with diabetes at 2 months of age, following a pregnancy complicated by gestational hypertension. She was initially treated with glibenclamide/metformin (2.5/500 mg) before breakfast. Due to inadequate metabolic control, her regimen was switched after 3 months to NPH insulin (16 IU sc at 7 am), and regular insulin (3 IU sc at lunch). This adjustment led to episodes of hypoglycemia, prompting the discontinuation of bolos insulin and a transition to insulin glargine (24 IU sc at 9 pm). At the time of admission, her hemoglobin A1c was 7.97%, with a glucose level of 93 mg/dl, a C-peptide of 0.07 ng/mL, and negative antibodies. The estimated probability of MODY was 12.6% (≥10% for insulin-treated patients). Given her clinical profile, which was inconsistent with typical T2D, whole exome sequencing (WES) was performed, revealing a pathogenic missense variant c.4135C>T (p.Arg1379Cys) in the
The third case was a 45-year-old female South-American Ecuadorian who was diagnosed with gestational diabetes during her first pregnancy at 12 weeks of gestation, at 19 years old. At the time of diagnosis, her BMI was 20 kg/m2, and she did not experience ketoacidosis. However, her hyperglycemia persisted after postpartum, indicating the development of permanent diabetes. Upon admission to the clinic, the patient was being treated with glargine and regular insulin, achieving optimal metabolic control with fasting blood glucose levels of 107 mg/dL and hemoglobin A1c of 6.85%. Her C-peptide was markedly reduced at 0.18 ng/mL. Testing for diabetes-associated antibodies was negative. She reported a strong family history of apparent type 2 diabetes, affecting her mother, aunts, cousins, and grandmother. Her MODY probability calculator score was 12.6%. Genetic analysis confirmed the presence of a pathogenic frameshift variant, in the
A 21-year- old male South-American Ecuadorian, product of a first gestation, with a perinatal history of small for gestational age (SGA) status, was diagnosed with apparent type 2 diabetes at the age of 13 years. One year later, he was additionally diagnosed with epilepsy and autism spectrum disorder. At 18 years of age, he was referred to our service for further evaluation. On physical examination, his BMI was 15.8 kg/m2, and relevant findings included microcephaly and right-sided hemiparesis. He had no history of diabetic ketoacidosis. Laboratory assessment revealed a C-peptide level of 1.0 ng/mL, with plasma glucose of 130 mg/dL, and islet autoantibodies were negative. The patient had never received pharmacological treatment for his diabetes. Family history included an 11-year-old brother diagnosed with diabetes. According to the Exeter MODY probability calculator, his score was 75.5%, indicating a high likelihood of monogenic diabetes. Genetic testing identified a likely pathogenic missense variant, c.613G>T (p.Asp205Tyr), in the
A 17-year-old male American Ecuadorian patient, with a paternal history of type 2 diabetes presented with hyperglycemia without ketoacidosis at 8 years, when he was diagnosed with type T1D and was started on intermediate acting insulin NPH with poor adherence. At age 17, he came to the emergency room with a 2-month history of facial and lower limb edema. Laboratory tests showed a fasting glucose of 472 mg/dL, hemoglobin A1c of 18.66%, and detectable C peptide at 0.64 ng/mL. Ketones were negative. Glutamic acid decarboxylase (GAD) and tyrosine phosphatase islet antigen-2 autoantibodies were negative. He also had glomerular hyperfiltration (CKD-EPI 188 mL/min/1.73 m2) and proteinuria close to nephrotic range (2902 mg/24 h). WES study was performed where a pathogenic missense variant, c.94G>A (p.Gly32Ser), in the
Maturity-Onset Diabetes of the Young (MODY) encompasses genetically heterogeneous, autosomal dominant forms of diabetes characterized by impaired insulin secretion due to pancreatic beta-cell dysfunction (
Despite the well-defined molecular underpinnings of MODY, the absence of a standardized diagnostic algorithm contributes to diagnostic delays and therapeutic mismanagement. A comprehensive diagnostic approach involves detailed clinical evaluation, diabetes-specific laboratory testing, and confirmatory genetic analysis to identify the causative mutation (
Given the natural history of MODY, the availability of cost-effective treatment options, and its potential impact on multiple family members, early and accurate diagnosis is essential. The presence of a positive family history, clinical features inconsistent with type 1 or type 2 diabetes, and the absence of diabetes-associated autoantibodies support the consideration of MODY in the differential diagnosis (
In our study we identified five patients with MODY. The median age at diabetes diagnosis was 13.6 years, while the median age at confirmed MODY diagnosis was 25.8 years, resulting in an average diagnostic delay of 12.2 years. This finding aligns with existing literature, which reports that the diagnosis of MODY is often delayed by more than 10 years after the initial presentation of diabetes (
Clinical misclassification remains a key challenge. Patients 1 (with an
Patients 2 and 4 were initially diagnosed with T2D as they did not require insulin therapy; patient 2 harboring an
Patient 3 carrying a
The MODY probability calculator, developed by the University of Exeter, has been validated as a screening tool for MODY diagnosis. A probability score of ≥20% for non-insulin-treated individuals and ≥10% for insulin-treated individuals indicate the necessity for genetic testing as per the National Health Services (NHS) England guidelines (
Identifying specific subtypes of MODY is crucial for implementing precision therapy, as each subtype responds differently to treatment based on its genetic cause. For instance, the correct identification of
Similarly, patients with
To date, the largest MODY registry from Latin America includes 104 patients from Brazil (
Although our case series is limited in size, it revealed both common and rare MODY subtypes, reflecting the genetic and phenotypic heterogeneity of monogenic diabetes. These findings underscore the importance of maintaining a high index of suspicion for MODY in patients with atypical diabetes presentations, regardless of the presence or absence of a family history. Accurate diagnosis, supported by WES, enabled personalized therapeutic adjustments in most cases, reinforcing the clinical value of genetic testing. Expanding access to molecular diagnostics and promoting clinician awareness are critical steps toward reducing diagnostic delays and improving outcomes. Further multicenter studies with larger cohorts are needed to validate these findings and enhance our understanding of the MODY spectrum in Latin American populations.
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article material.
The study was conducted in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the patients for the publication of this case report.
RR-U: Conceptualization, Formal analysis, Funding acquisition, Methodology, Supervision, Validation, Writing – review & editing. DM-M: Formal analysis, Methodology, Validation, Writing – review & editing. MV-E: Formal analysis, Methodology, Validation, Writing – review & editing. CR-S: Formal analysis, Validation, Writing – original draft. JS-V: Validation, Writing – original draft. GJ-K: Validation, Writing – original draft. DS-C: Validation, Writing – original draft. EG-I: Funding acquisition, Methodology, Supervision, Writing – review & editing.
The author(s) declare that financial support was received for the research and/or publication of this article. EG-I received a María Zambrano Program fund from the European Union, Spain.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declare that no Gen AI was used in the creation of this manuscript.
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