Maturity Onset Diabetes of the Young (MODY) Panel

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. As this non-insulin dependent type of diabetes is frequently misdiagnosed as type 1 or type 2 diabetes, a timely and accurate molecular diagnosis of MODY is essential to treatment decisions, prognosis, family screening, and obstetric management of gestational diabetes (Ellard et al. 2008. PubMed ID: 18297260). MODY has been conventionally classified into 14 types in terms of the causative genes.

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, NEUROD1, and RFX6), glucokinase (GCK, a glucose sensor in pancreatic beta-cells), insulin (INS), kinase stimulating insulin synthesis and secretion (BLK), the enzyme carboxyl ester lipase (CEL), the ATP-sensitive potassium (KATP) channels (ABCC8 and KCNJ11), and a protein involved in glucose metabolism (APPL1). Our current MODY panel covers all of these genes.

This panel also includes the WFS1 gene, which is known to be associated with Wolfram syndrome characterized by diabetes mellitus, optic atrophy, diabetes insipidus, and deafness. Increased evidence showed that recessive pathogenic WFS1 pathogenic variants can cause non-syndromic monogenic diabetes (Li et al. 2020. PubMed ID: 31658956; Zalloua et al. 2008. PubMed ID: 18806274). WFS1 encodes a transmembrane glycoprotein termed wolframin, which is required for the normal functioning of endoplasmic reticulum (ER).

This panel also includes the GLUD1 and HADH genes, both of which are associated with familial hyperinsulinism. Hyperinsulinism-hyperammonemia syndrome is the second most common type of congenital hyperinsulinism (CHI) and is caused by dominant, activating mutations in the GLUD1 gene, which encodes glutamate dehydrogenase (GDH). This enzyme is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. The HADH gene encodes short-chain L-3-hydroxyacyl-CoA dehydrogenase, a fatty acid oxidation enzyme in the mitochondrial matrix. Recessive, inactivating HADH pathogenic variants can cause CHI (Clayton et al. 2001. PubMed ID: 11489939).

Pathogenic variants in HNF1A, HNF4A, GCK, and HNF1B genes account for over 80% of all known MODY cases while defects in other genes are rare causes of MODY (Owen. 2013. PubMed ID: 23760703). Genetic defects throughout the genes in this panel include missense and various truncating variants (nonsense, splicing variants, and small deletions or insertions) (Human Gene Mutation Database). Exon-level large deletions or duplications have been found in these genes: HNF1A, HNF4A, HNF1B, GCK, INS, ABCC8, and WFS1 (Human Gene Mutation Database). De novo variants are not uncommon in MODY genes, especially in HNF1A, HNF4A, GCK, and HNF1B (Stanik et al. 2014. PubMed ID: 24323243; Heidet et al. 2010. PubMed ID: 20378641).

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

Over 80% of all known maturity onset diabetes of the young (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 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 with non-syndromic, non-autoimmune diabetes mellitus (~1.2%) (Zalloua et al. 2008. PubMed ID: 18806274).

Exon-level large deletions have been found in the HNF1A, HNF4A, HNF1B, GCK, INS, ABCC8, and WFS1 genes (Human Gene Mutation Database). However, our internal data suggests copy number variants are relatively uncommon in the genes of this panel.

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

This panel typically provides 95.9% 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).

Due to technical difficulties, exons 1, 8-9, and 11 of the CEL gene are not included in this panel. Pathogenic variants in the VNTR of CEL are a rare cause of MODY (Torsvik et al. 2010. PubMed ID: 19760265; Fjeld et al. 2015. PubMed ID: 25774637).

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).