Monogenic Diabetes Panel

Monogenic diabetes is a clinically and genetically heterogeneous group of disorders due to pathogenic variants in a single gene, accounting for approximately 2% of people with diabetes (Harris et al. 2018. PubMed ID: 29846255). Monogenic diabetes includes maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM), as well as rarer syndromic diabetes such as monogenic forms of autoimmunity. Genetic testing for monogenic diabetes is critical for personalized treatment, since many patients can be misdiagnosed with type 1 or type 2 diabetes.

Maturity onset diabetes of the young (MODY), a primary pancreatic beta-cell defect, is the most common type of monogenic diabetes, accounting for up to 5% of young adults diagnosed with diabetes (Owen. 2013. PubMed ID: 23760703; McDonald and Ellard. 2013. PubMed ID: 23878349). MODY typically presents in lean young adults before 25 years with an autosomal dominant family history. MODY patients have continued production of endogenous insulin, absence of beta-cell autoimmunity, and absence of signs of insulin resistance. MODY has been conventionally classified into 14 types in terms of the causative genes.

Neonatal diabetes mellitus (NDM), also termed congenital diabetes or infancy-onset diabetes, has an estimated incidence of 1 out of 100,000 live births. It is typically diagnosed within the first six months of life (Harris et al. 2018. PubMed ID: 29846255). NDM consists of two forms: permanent and transient. The common symptoms of NDM include hyperglycemia, polyuria, tachypnea, tiredness, and dehydration. The transient form typically resolves by 18 months of age, while the permanent form requires lifelong treatment.

In diabetes occurring within 12 months of age, monogenic forms of autoimmunity-related diabetes are a subgroup that have positive pancreatic autoantibodies but are caused by defects in single genes. These monogenic autoimmune syndromes have highly variable phenotypes. Further investigation of these disorders may help discriminate them from type 1 diabetes and determine guidelines for genetic testing and treatment (Harris et al. 2018. PubMed ID: 29846255).

Monogenic diabetes is a clinically and genetically heterogeneous group of disorders that can be inherited in an autosomal dominant (including de novo), autosomal recessive, or X-linked manner. Causative variants include missense, nonsense, splicing, regulatory, and copy number alterations.

MODY is inherited in an autosomal dominant manner. Proteins encoded by MODY-associated genes include nuclear transcription factors controlling pancreatic development (HNF1A, HNF4A, HNF1B, PDX1, KLF11, PAX4, and NEUROD1); glucokinase, a glucose sensor in pancreatic beta-cells (GCK); insulin (INS); a kinase stimulating insulin synthesis and secretion (BLK); the enzyme carboxyl ester lipase (CEL); the ATP-sensitive potassium (KATP) channels (ABCC8 and KCNJ11); and glucose metabolism (APPL1).

For permanent neonatal diabetes mellitus (PNDM), dominant heterozygous pathogenic variants in KCNJ11 are the most common cause, followed by INS (dominant and recessive), ABCC8 (recessive), and GCK (recessive). Recessive variants in EIF2AK3, INS, and GCK are more common in consanguineous families (De Franco et al. 2015. PubMed ID: 26231457). For transient neonatal diabetes, 70% of cases have a methylation abnormality in the 6q24 region while pathogenic variants in other genes such as ABCC8, KCNJ11, INS, or HNF1B have also been reported (Harris et al. 2018. PubMed ID: 29846255). 

The causative genes for diabetes-related monogenic forms of autoimmunity include FOXP3, IL2RA, LRBA, STAT1, and STAT3. Encoding a transcription factor (FOXP3), cell surface receptor (IL2RA), endosomal trafficking protein (LRBA), and STAT protein family members (STAT1 and STAT3), these genes play a vital role in maintaining the immune system (OMIM).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants. 

Over 80% of all known MODY cases in the UK are caused by defects in HNF1A (~30%), HNF4A (~10%), GCK (~30%), or HNF1B (5-10%) (Owen. 2013. PubMed ID: 23760703). In the UK, HNF1A-MODY is the most common form in adults while GCK-MODY is the most common form in children.

In a large genomic screen study of 4,016 patients diagnosed with type 2 diabetes, nearly 2% of patients with early-onset (<40 years) disease were found to have pathogenic variants in MODY genes (Bansal et al. 2017. PubMed ID: 29207974).

In exome sequencing of 82 Chinese Han patients clinically diagnosed with type 1 diabetes but who were negative for three autoantibodies, 18 (~22%) patients were found to have plausibly pathogenic variants in MODY genes (14 cases; ~17%) or the WFS1 gene (4 cases; ~5%) (Li et al. 2020. PubMed ID: 31658956). In 399 probands with juvenile-onset diabetes in Lebanon, homozygous or compound heterozygous WFS1 variants were found in five patients (~1.25%) with non-syndromic non-autoimmune diabetes mellitus (Zalloua et al. 2008. PubMed ID: 18806274).

In a large international (79 countries) cohort study (1020 patients; 571 boys and 449 girls) of patients with neonatal diabetes diagnosed before six months of age, causal variants were identified in more than 80% of cases (De Franco et al. 2015. PubMed ID: 26231457).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.8% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).