Maturity Onset Diabetes of the Young (MODY) and Permanent Neonatal Diabetes Mellitus (PNDM) via the INS 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 optimal 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 INS 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). INS pathogenic variants are a major cause of PNDM through an autosomal dominant or recessive inheritance (Støy et al. 2007; Garin et al. 2010). Patients with recessive INS variants had a lower birth weight and were diagnosed earlier compared to those with dominant INS pathogenic variants (Garin et al. 2010).

The INS gene (2 coding exons) encodes insulin, the hormone regulating blood glucose level. Dominant-acting INS pathogenic variants cause both MODY and PNDM due to proinsulin misfolding while recessive-acting pathogenic variants cause PNDM due to reduced synthesis of the preproinsulin peptide (Meur et al. 2010; Støy et al. 2007; Garin et al. 2010).

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) (Ellard et al. 2008; McDonald et al. 2013). INS pathogenic variants cause MODY10 (Molven et al. 2008; Meur et al. 2010). Heterozygous INS pathogenic variants found in MODY so far only include missense changes (Human Gene Mutation Database).

INS-PNDM can be inherited dominantly or recessively (Støy et al. 2007; Garin et al. 2010). Genetic defects of INS found in PNDM so far include missense, nonsense, regulatory, splicing mutations, small indels and large deletions (Human Gene Mutation Database). The other two major causative genes for PNDM are ABCC8 and KCNJ11 (Molven et al. 2011).

INS defects are a rare cause of MODY (Molven et al. 2011). The INS mutation detection rate in a large cohort of MODY patients is unknown because these mutations were only reported in a limited number of patients. In 279 patients with PNDM, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively (Edghill et al. 2008).

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

This test provides full coverage of all coding exons of the INS gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.