Maturity Onset Diabetes of Young (MODY) and Permanent Neonatal Diabetes Mellitus (PNDM) via the NEUROD1 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). Heterozygous NEUROD1 pathogenic variants are a rare cause of MODY.

Within the spectrum of neonatal diabetes mellitus, permanent neonatal diabetes mellitus (PNDM) represents the severe end of hyperglycemia. In addition to neonatal diabetes, PNDM patients have neurological complications including developmental delay, epilepsy, cerebellar hypoplasia, learning difficulties, sensorineural deafness, and visual impairment (Molven et al. 2011). Homozygous loss of function NEUROD1 variants are a rare cause of PNDM (Rubio-Cabezas et al. 2010).

The NEUROD1 gene (1 coding exon) encodes a member of the NeuroD family of basic helix-loop-helix (bHLH) transcription factors, which plays a role in neuronal differentiation and pancreatic morphological development.

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). NEUROD1 pathogenic variants cause MODY6 (Malecki et al. 1999; Kristinsson et al. 2001). Heterozygous NEUROD1 variants found in MODY so far only include missense changes and small deletion/insertions (Human Gene Mutation Database).

NEUROD1-PNDM is inherited recessively, and only limited cases have been reported (Rubio-Cabezas et al. 2010). Genetic defects of NEUROD1 found in PNDM so far only include small deletions/insertions (Human Gene Mutation Database). The major causative genes for PNDM are ABCC8, KCNJ11 and INS (Molven et al. 2011).

NEUROD1 defects are a rare cause for both MODY and PNDM (Molven et al. 2011). The NEUROD1 mutation detection rates in a large cohort of patients are unknown because these mutations have only been reported in a limited number of patients.

This test provides full coverage of all coding exons of the NEUROD1 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).