EP762 - ECE_3163 - Variant of uncertain significance in IRS 2 gene in patient with diabetes mellitus—case report
TL;DR
A variant of uncertain significance (VUS) is a genetic variant identified during genetic testing but whose significance to clinical presentation is not known that can possibly lead to disease development and remains important both for carrier monitoring and for further genetic counseling.
Abstract
A variant of uncertain significance (VUS) is a genetic variant identified during genetic testing but whose significance to clinical presentation is not known. Insulin receptor substrate 2 (IRS2) is important for pancreatic beta-cell survival and function, reduction of peripheral insulin sensitivity and insulin signaling. A17 year old female patient was referred to endocrinologist because of high fasting blood glucose levels measuring up to 19 mmol/L. Her symptoms were present for two weeks and included fatigue, mouth dryness and polyuria. Prenatal and early childhood medical history were unremarkable. Her father was diagnosed with type 2 diabetes mellitus (T2DM) at the age of 40 years. Initial laboratory findings were: HbA1c 12.5%, C peptides 1.6 ng/ml. She was started with insulin therapy with oral antidiabetics (Metformin). After 3 months, HbA1c was 6.4%. She was positive for GAD (Glutamic Acid Decarboxylase) autoantibodies 26.3 U/ml, while ICA (Islet Cell Antibodies), IA-2 (Insulinoma-Associated Antigen 2) and ZnT8 (Zinc Transporter 8) autoantibodies were negative. After one year, HbA1c was 7.5% and C peptides levels were 2.6 ng/ml. Autoantibodies were negative. Since it is possible to find positive autoantibodies in 1% of MODY patients, MODY was suspected and clinical genome sequencing was requested. The result was undetermined, since one heterozygous VUS with a 67.5% probability of pathogenicity leading to diabetes mellitus was detected in the IRS2 gene. The genetic heterozygous missense variant c.4012G>A, p.(Glu1338Lys) in the IRS2 gene replaces the amino acid glutamic acid with the amino acid lysine at position 1338 of the polypeptide chain. According to the American College of Medical Genetics and Genomics classification criteria, the detected variant in the IRS2 gene is classified as VUS – class 3. This variant was not found in either the gnomAD genomes or the gnomAD exomes (PM2_Supporting) and is predicted to result in alternative splicing and loss of function in IRS2. This disease is inherited in an autosomal dominant manner and can lead to T2DM. A father and younger sister are also tested and pending results. After three years since first being diagnosed the patient is on insulin therapy with C peptide 1.6ng/ml and HbA1c 6.3%. A variant of uncertain significance (VUS) can possibly lead to disease development and remains important both for carrier monitoring and for further genetic counseling. A VUS found in IRS 2 gene can lead to development of diabetes mellitus.