Maturity Onset Diabetes of the Young (MODY) via the APPL1 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. 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 causative genes. The APPL1 gene was reported to cause familial diabetes mellitus due to heterozygous loss-of-function variants (Prudente. 2015. PubMed ID: 26073777).

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), the ATP-sensitive potassium (KATP) channels (ABCC8 and KCNJ11) and glucose metabolism (APPL1).

The APPL1 gene (22 coding exons) encodes the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1, which plays a key regulatory role in glucose metabolism. To date, only two loss-of-function variants (a missense and a nonsense variant) in APPL1 have been reported to cause familial diabetes mellitus (Prudente. 2015. PubMed ID: 26073777). Large deletions and duplications have not been reported (Human Gene Mutation Database).

In a whole-exome sequencing study of 60 families with familial diabetes mellitus but without pathogenic variants found in the six most common MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B and NEUROD1), heterozygous pathogenic variants in APPL1 were detected in two families (3.3%) (Prudente. 2015. PubMed ID: 26073777).

This test provides full coverage of all coding exons of the APPL1 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).