Maturity Onset Diabetes of the Young (MODY) via the HNF4A Gene

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; McDonald et al. 2013). 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). MODY has been conventionally classified into 11 types in terms of the causative genes (Molven et al. 2011). HNF4A-MODY (MODY1) presents with a progressive insulin secretory defect and hyperglycaemia that can lead to the development of vascular diabetic complications (McDonald et al. 2013).

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), the glucokinase (a glucose sensor in pancreatic beta-cells) (GCK), insulin (INS), kinase stimulating insulin synthesis and secretion (BLK), the enzyme carboxyl ester lipase (CEL), and the ATP-sensitive potassium (KATP) channels (ABCC8 and KCNJ11) (Ellard et al. 2008; McDonald et al. 2013).

Defects in the HNF1A, HNF4A, GCK and HNF1B genes account for over 80% of all known MODY cases.

The HNF4A gene (10 coding exons) encodes hepatocyte nuclear factor 4-alpha. Alongside other hepatic nuclear transcription factors, it regulates the expression of insulin as well as altering beta-cell development, proliferation and cell death in the mature beta-cells. Genetic defects of HNF4A found so far include missense, nonsense, splicing, regulatory variants, small deletion/insertions and gross deletions (Human Gene Mutation Database).

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

This test provides full coverage of all coding exons of the HNF4A gene 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 full 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).