Maturity-Onset Diabetes of the Young (MODY) NGS Panel

Clinical Information

Maturity-onset diabetes of the young, or MODY, typically presents in adolescents or young adults under the age of 25. The features of this condition are atypical for both type 1 and type 2 diabetes mellitus as MODY is not usually associated with obesity, acanthosis nigricans, or hyperecholesterolemia, and response to insulin use for hyperglycemia is limited. MODY has an estimated prevalence of 1 in 10,000 adults with approximately 1-2% of all diabetics having this form.

Patients with pathogenic variants in the HNF1A and HNF4A genes sometimes experience a worsening of hyperglycemia over time and may eventually require insulin for treatment. However, many individuals with MODY only require oral medications, while others have a stable level of hyperglycemia and may not need treatment at all. MODY is inherited in an autosomal dominant pattern in the majority of cases, and familial hyperinsulinism often shows lower penetrance than MODY. Confirmation of pathogenic variants can assist with accurate diagnosis and treatment as well as testing for other at-risk family members.

Technical Information

This panel is performed by Next Generation Sequencing and covers the coding regions of the listed genes and the flanking intronic sequences. Promoter, 3′ untranslated sequences, and deep intronic sequences are also covered, but only known disease-causing variants in these regions will be reported. Variants identified on the panel are confirmed with Sanger sequencing if they do not meet certain quality thresholds. Large deletions and duplications (CNVs) affecting the genes of the panel can be detected; however, due to defined settings in the analysis software, CNVs smaller than 2-kb may not be identified (for example, some small exonic level copy number changes may not be identified).

Please note that certain types of genetic alterations including trinucleotide repeat expansions, methylation abnormalities, and balanced rearrangements (e.g., inversions, reciprocal translocations) may not be detected by the current analysis. The variant analyzed in the MT-TL1 gene is m.3243A>G. Pathogenic variants in the HNF1A gene are identified in 30-65% of patients with MODY, and alterations in the GCK gene account for an additional 30-50% of cases. Changes in the HNF4A and HNF1B genes are responsible for at least 5% each with alterations in the remaining genes contributing to a small percentage of affected individuals. Exons 1, 8, 9, and 11 of the CEL gene are not analyzed due to high sequence identity with a pseudogene. Contact the laboratory if there is a concern for a sequence variant in these exons.

Specimen Requirements

• The preferred sample type is 3-4 ml of peripheral blood collected in an EDTA (purple top) tube. Extracted DNA and saliva are also accepted for this test. Blood and saliva kits are available by request.
• Send approximately 5µg of extracted DNA at a requested concentration of 90-130 ng/µl.
• Saliva samples must be submitted in an approved saliva kit. If saliva is submitted, and the extracted DNA is below quality control, then you will be contacted to submit a blood sample or the panel can be completed on an exome backbone.

Transport Instructions

• The blood specimen should be kept at room temperature and delivered via overnight shipping. If shipment is delayed by one or two days, the specimen should be refrigerated and shipped at room temperature. Do not freeze the specimen. Samples collected on Friday can be safely designated for Monday delivery.
• Extracted DNA should be sent at room temperature via overnight delivery.
• Saliva is stable at room temperature and can be delivered via overnight or ground shipping.