Pages Navigation Menu

Monogenic Diabetes

Monogenic Diabetes (MDM) is diabetes caused by specific identifiable defects in particular genes or areas within genes (known as chromosome loci). More than 50 genetic variants have now been reported (at the time of this page update) with the genetic defects affecting different, but specific, aspects of insulin secretion or insulin action.

An important feature of these disease-causing genetic mutations is that they appear to be minimally affected by behavioral and environmental factors.

There are numerous types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, and multiple causes of neonatal diabetes, and syndromic diabetes such as Wolfram syndrome and lipodystrophy.

What’s covered on this page:

Monogenic vs Polygenic Diabetes
Genetic Research
Maturity Onset Diabetes of the Young (MODY)
Neonatal Diabetes
Insulin Resistance Syndromes
Diagnosis and Classification of Monogenic forms of Diabetes
Genetic Testing

Monogenic vs. Polygenic Diabetes

Monogenic diabetes is caused by a single gene mutation that has a strong effect, while polygenic diabetes results from multiple genetic variants with smaller effects, influenced by environmental and lifestyle factors. In Type 1 diabetes (T1DM), the main issue is an autoimmune response that destroys insulin-producing cells, with genetic and environmental factors playing a role. Monogenic diabetes causes severe problems with insulin production, leading to diabetes regardless of other factors. Type 2 diabetes (T2DM) is a complex condition, often related to insulin resistance and influenced by multiple genetic factors and lifestyle. While this distinction is helpful, new research is showing that diabetes genetics exist on a spectrum, with varying degrees of genetic impact.

NOTE

As this field of research continues to evolve, ‘monogenic’ and ‘polygenic’ forms of diabetes are now joined by conditions in which two (‘digenic’) or a few (‘oligogenic’) genes with variant alleles contribute to inherited forms of diabetes. [It’s almost impossible to keep up!] Often, these genes cluster in shared pathways, compounding the effect of multiple genes that individually might not cause clinically significant disease.

Genetic Research

Maturity Onset Diabetes of the Young (MODY) was first recognised back in 1974 when this dominantly inherited form of diabetes was originally reported as “mild familial diabetes with dominant inheritance”. Subsequently ‘maturity-onset diabetes of the young’ was used to distinguish this form from juvenile onset Type 1 diabetes and indicate its similarities in clinical presentation to maturity-onset diabetes (now known as Type 2)

MODY has since been a major focus for genetic research, and along the way this has informed the development of new medications for Type 2 diabetes, and is now paving the way for personalised or ‘precision’ medicine for people living with these types of diabetes.

1990s: Early Discovery Phase

Initial Concept: MODY was recognized as a monogenic form of diabetes, distinct from Type 1 and Type 2 diabetes. It typically presents in adolescence or early adulthood and is inherited in an autosomal dominant pattern.
First Genes Identified:
- HNF1A (MODY3) and GCK (MODY2) were among the first genes linked to MODY.
- Mutations in these genes helped establish the idea that single-gene defects could cause diabetes by affecting insulin production or glucose sensing.

2000s: Expansion of Genetic Subtypes

In 2001, the Human Genome Project published the first complete sequence for the human genome, and with that, sparked a new era in genetic discoveries.
More MODY Genes Identified: Additional genes associated with MODY were discovered, including:
- HNF4A (MODY1)
- PDX1 (MODY4)
- HNF1B (MODY5)
- NEUROD1 (MODY6)
Functional Insights: Research focused on how these gene mutations impair β-cell development, insulin secretion, or glucose sensing.
Genetic Testing: Became increasingly available, allowing for better diagnosis and differentiation from Type 1 or Type 2 diabetes.

2010s: Clinical Integration & Precision Medicine

Diagnostic Precision: Genetic testing was more widely integrated into clinical practice.
Treatment Tailoring:
- Patients with HNF1A and HNF4A mutations often respond well to sulfonylureas, avoiding insulin.
- GCK-MODY generally does not require pharmacological treatment.
Registry and Cohort Studies: Large MODY registries and global collaborations helped define the clinical spectrum of each subtype.

2020s to date: Advances in Genomics & Personalized Care

Next-Generation Sequencing (NGS): Enabled more comprehensive and cost-effective gene panels and exome sequencing for MODY and other monogenic diabetes.
Variants of Uncertain Significance (VUS): Became a challenge; ongoing work aims to improve interpretation using functional assays and AI tools.
Newly Proposed MODY Genes: Emerging candidates such as KLF11, CEL, and BLK, although not all are universally accepted.
Ethnic Diversity: More studies included underrepresented populations, improving understanding of MODY prevalence and genetic variation globally.

Maturity Onset Diabetes of the Young (MODY)

MODY comprises the largest proportion of monogenic diabetes. Common characteristics include young diagnosis age, family history of diabetes in an autosomal dominant pattern of transmission, and insulin independence.

To date, 14 different MODY genes have been suggested; of these 11 have been confirmed.

For more info on specific MODY genes identified to date, click here

Neonatal Diabetes (NDM)

Neonatal Diabetes (NDM) is diabetes that is diagnosed within the first 6-9 months of age. It may be either permanent (PNDM) or transient (TNDM).

Features of NDM may include slow growth before birth (intrauterine growth restriction), poor weight gain after birth (failure to thrive), increased urination (polyuria), and significant dehydration.. Depending on the genetics, some babies may also have birth defects and/or neurological disorders.

These types of diabetes are rare. Research data suggests that NDM affects approximately 1 in 90,000 to 260,000 live births, 50% of which will be transient (i.e. TNDM) and 50% permanent (i.e. PNDM).

For specific NDM genes genes identified to date, click here

Insulin Resistance Syndromes

Syndromic Monogenic Diabetes encompasses patients where their diabetes occurs as part of a monogenetic syndrome with characteristic extra-pancreatic features (caused by mutations in one of 18 different genes).

Such genetic defects in insulin action include:

Type A insulin resistance
Donohue syndrome (Leprechaunism)
Rabson-Mendenhall syndrome
Lipoatrophic diabetes

For specific Insulin Resistance Syndrome genes identified to date, click here

Diagnosis of Monogenic Diabetes

An accurate genetic diagnosis may be important in order to ensure appropriate treatment.

Here in Aotearoa New Zealand, there is publicly funded access to genetic testing for monogenic diabetes through Hospital and Specialist Services (HSS) – usually via an endocrinologist. National guidelines for monogenic diabetes genetic testing published by the New Zealand Society for the Study of Diabetes (NZSSD) currently require clinical identification of potentially affected individuals based on the absence of typical features for type 1 diabetes (i.e. absence of auto-antibodies, persistence of significant C-peptide) or type 2 diabetes (e.g. absence of obesity, hypertension, hyperlipidaemia).

Why is Genetic Testing Important?

Genetic testing can confirm if your diabetes is caused by a single gene change. This is particularly important for children and babies over the age of 9 months:

It can lead to a more accurate diagnosis.
It might mean a change in your treatment (e.g. switching from insulin to tablets).
It can help other family members understand their risk.
It may explain why diabetes appears in your family at a young age.

At the moment, this testing is only available through hospital specialists (secondary care), and you may need a referral from your GP or diabetes team.

What is Cascade Testing?
Cascade testing means offering genetic testing to your family members once a gene change is found. This helps find out who else may have or be at risk of monogenic diabetes. Early diagnosis can lead to better management and peace of mind.

What Should I Know About the Results?
Genetic testing results can sometimes be complex:

Positive result – A gene change that explains your diabetes is found.
Negative result – No gene change is found, or it’s not the cause of your diabetes.
Uncertain result (VUS) – A change is found, but we don’t yet know if it causes diabetes.

Some gene changes don’t always cause diabetes (this is called low penetrance), and some people may show features of both monogenic and type 2 diabetes. That’s why it’s important to get support from trained professionals.

Genetic Counselling: What to Expect
Before and after testing, you may be offered genetic counselling. This is a chance to:

Learn what the test can and can’t tell you
Ask questions about how results may affect you or your family
Get support in making decisions about testing and next steps

Genetic counsellors and specialist nurses are there to guide you through the process and explain everything clearly.

Need More Help?
If you think monogenic diabetes might apply to you or your family, speak to your GP or diabetes team. They can refer you for further advice and testing if needed.