What are the recommended screening tests for Maturity-Onset Diabetes of the Young (MODY)?

Recommended Screening Tests for Maturity-Onset Diabetes of the Young (MODY)

Genetic testing is the definitive screening test for diagnosing MODY and should be performed in individuals who have atypical diabetes and multiple family members with diabetes not characteristic of type 1 or type 2 diabetes. 1

Clinical Criteria for MODY Screening

MODY should be suspected in patients with:

• Young age of diabetes onset (typically before 25-30 years) 1, 2
• Autosomal dominant inheritance pattern (diabetes in multiple generations) 2
• Absence of pancreatic islet autoantibodies 1
• Preserved beta-cell function (detectable C-peptide) 3
• Non-obese body habitus 2, 4
• Stable, mild fasting hyperglycemia (100-150 mg/dL) 2
• A1C typically between 5.6-7.6% (38-60 mmol/mol) 2

Initial Biomarker Screening

Before proceeding to genetic testing, the following screening tests should be performed:

1. Pancreatic autoantibody testing (GAD, IA-2, ZnT8) - negative results support MODY diagnosis 1
2. C-peptide measurement - preserved levels (especially with glucose >144 mg/dL) suggest MODY rather than type 1 diabetes 3
3. Urinary C-peptide/creatinine ratio - useful biomarker for identifying MODY 2
4. High-sensitivity CRP (hs-CRP) - low levels may specifically suggest HNF1A-MODY 2

Genetic Testing Approach

When clinical criteria suggest MODY:

1. Next-generation sequencing panel targeting known MODY genes is the preferred testing method 1, 2
2. Focus on the most common mutations:
   • GCK (MODY2)
   • HNF1A (MODY3)
   • HNF4A (MODY1)
   • HNF1B (MODY5) 2

Important Considerations

• Genetic testing is increasingly available and cost-effective 1

• Correct diagnosis is critical as it leads to:

  • More appropriate treatment (no therapy for GCK-MODY; sulfonylureas as first-line for HNF1A-MODY and HNF4A-MODY) 1
  • Identification of affected family members 1
  • Prevention of misdiagnosis as type 1 or type 2 diabetes 5

• The diagnostic yield of genetic testing in clinically suspected MODY is approximately 40% 6

Pitfalls to Avoid

• The presence of autoantibodies generally precludes MODY diagnosis, but rare cases of autoantibody positivity in monogenic diabetes have been reported 1
• Not all rare variants detected in MODY genes are pathogenic; approximately 15% may be variants of uncertain significance 6
• Misdiagnosis of MODY as type 1 or type 2 diabetes is common and can lead to suboptimal treatment 5

After Diagnosis

• Consultation with a center specializing in diabetes genetics is recommended for:
  • Interpretation of genetic test results
  • Treatment guidance
  • Genetic counseling 1, 2
• Genetic counseling should be provided to ensure affected individuals understand inheritance patterns and the importance of correct diagnosis 1

Following this structured approach to MODY screening will help identify patients with monogenic diabetes, leading to more appropriate treatment strategies and improved outcomes for both patients and their family members.