Maturity Onset Diabetes of Young (MODY) via the PDX1 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 causative genes (Molven et al. 2011).

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), kinase stimulating insulin synthesis and secretion (BLK), the enzyme carboxyl ester lipase (CEL), and the ATP-sensitive potassium (KATP) channels (ABCC8 and KCNJ11). The PDX1 gene (also known as IPF1; 2 coding exons) encodes a homeodomain-containing transcription factor, which plays a major role in glucose-dependent regulation of insulin gene expression. Recessive PDX1 mutations cause pancreatic agenesis leading to neonatal diabetes mellitus while dominant PDX1 mutations cause MODY4 (Stoffers et al. 1997). Causative genetic defects of PDX1 found so far include missense, nonsense mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving PDX1 have not been reported.

Over 80% of all known MODY cases in the UK are caused by mutations 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 while GCK-MODY is the most common form in children. For the remaining genes associated with rare forms of MODY including PDX1, the mutation detection rates in a large cohort of patients are unknown because these mutations were only reported in a limited number of patients (families).

This test provides full coverage of all coding exons of the PDX1 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).