Diabetes, Hyperinsulinism and ER Stress

Genomics and Pathology Services (GPS) offers germline variant detection by next-generation sequencing in key genes implicated in genetic forms of diabetes, hyperinsulinism and endoplasmic reticulum stress.

Results can provide physicians with useful information to solidify a diagnosis, allowing for more appropriate patient management and surveillance. They also enable tailored genetic counseling in both the patient and at-risk family members.

REQUISITIONINFO SHEETGENES


Indications for Testing

Some more common indications for testing include symptoms of:

  • Children diagnosed with diabetes in the first 6 months of life
  • Individuals diagnosed with diabetes not characteristic of type 1 or type 2 diabetes
  • Family history of diabetes
  • Hypoglycemia that ranges from severe neonatal onset to childhood onset with mild symptoms
  • Patients suspected to have Wolfram Syndrome or WFS1 related disorders

 


Available Tests and Gene Lists

Rare and Atypical Diabetes Comprehensive Gene Set

53 genes sequenced including ABCC8, AGPAT2, AIRE, APPL1, AKT2, BLK, CACNA1D, CEL, CISD2, CP, EIF2AK3, FOXA2, FOXP3, GATA4, GATA6, GCK, GLIS3, GLUD1, HADH, HFE, HNF1A, HNF1B, HNF4A, IER3IP1, INS, INSR, KCNJ11, KDM6A, KLF11, KMT2D, LRBA, MNX1, NEUROD1, NEUROG3, NKX2-2, PAX6, PAX4, PCBD1, PDX1, PGM1, PLAGL1, PPARG, PTF1A, RFX6, PMM2, SLC2A2, SLC16A1, SLC19A2, STAT3, TRMT10A, UCP2, WFS1 and ZFP57.

Endoplasmic Reticulum (ER) Stress Gene Set

5 genes sequenced including CISD2, EIF2AK3, IER3IP1, INS and WFS1.

Hyperinsulinism Gene Set

18 genes sequenced including ABCC8, AKT2, CACNA1D, FOXA2, GCK, GLUD1, HADH, HNF1A, HNF4A, INSR, KCNJ11, KDM6A, KMT2D, PGM1, PMM2, SLC16A1, TRMT10A and UCP2.

Permanent Neonatal Diabetes Mellitus (PNDM) Gene Set

29 genes sequenced including ABCC8, CP, EIF2AK3, FOXP3, GATA4, GATA6, GCK, GLIS3, HNF1B, IER3IP1, INS, KCNJ11, LRBA, MNX1, NEUROD1, NEUROG3, NKX2-2, PAX6, PCBD1, PDX1, PLAGL1, PTF1A, RFX6, SLC2A2, SLC19A2, STAT3, TRMT10A, WFS1 and ZFP57.

Monogenic Diabetes and MODY Gene Set

43 genes sequenced including ABCC8, AGPAT2, AIRE, APPL1, AKT2, BLK, CEL, CISD2, CP, EIF2AK3, FOXP3, GATA4, GATA6, GCK, GLIS3, HFE, HNF1A, HNF1B, HNF4A, IER3IP1, INS, INSR, KCNJ11, KLF11, LRBA, MNX1, NEUROD1, NEUROG3, NKX2-2, PAX4, PAX6, PCBD1, PDX1, PLAGL1, PPARG, PTF1A, RFX6, SLC2A2, SLC19A2, STAT3, TRMT10A, WFS1 and ZFP57.


Testing Methodology

Tests are performed using targeted hybridization capture coupled with next-generation sequencing (NGS) in our CAP/CLIA labs for comprehensive coverage of all coding exons of ordered genes.

Types of variation detected include single nucleotide variants (SNVs) and small insertions and deletions (indels).

For some cases with negative results or isolated heterozygous mutations in recessive genes, additional testing by alternate methodology will be performed to determine the presence of rare variant types not detected by this assay.


Results and Interpretation

DNA sequence data are analyzed by GPS’ clinically validated bioinformatics pipeline to identify and annotate genetic variants associated with the phenotype(s).

Variants are interpreted by a board-certified clinical genomicist in the context of the patient’s disease. Those that are most likely to account for the observed clinical phenotype based on evidence from the medical literature are highlighted.

Results are returned to the ordering physician in a concise report.

The turnaround time for testing and interpretation is four to six weeks from the time a specimen arrives.


Specimen Requirements

Specimen types accepted include 2-5 mL peripheral blood in a lavender-top EDTA tube. Specimen collection kits are available upon request.

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Clinical Utility

Genetic variation within a number of genes has now been described in association with various forms of genetic diabetes.

Determination of the underlying genetic cause can aid in diagnosis and provide information of prognostic and therapeutic relevance.

Diagnosis – Observation of a known or expected pathogenic variant by genetic testing can solidify a clinical diagnosis allowing for appropriate patient management and surveillance and allows for screening of at-risk family members.

Prognosis – Genotype-phenotype relationships have been established in some forms of diabetes.

Knowledge of the causative genetic variant can provide information surrounding the genotype-specific natural history of the disease, response to pharmacotherapy, and symptom triggers.

Treatment – Therapeutic interventions exist for many forms of diabetes. Therapies may include drug or surgical interventions as appropriate for optimal patient management.