Balkan Journal of Medical Genetics

A CASE OF MODY 2 - ASSOCIATED HYPERGLYCEMIA DIAGNOSED AS GESTATIONAL DIABETES
Chakarova N.1, Balabanski L.2,3, Dimova R.1, Tsarkova P.1, Tankova T.1
*Corresponding Author: Nevena Chakarova, MD, PhD, Department of Endocrinology Medical University Sofia, 1431 Sofia, 2 Zdrave Str., e-mail: veni_chakarova@abv.bg, ORCID ID 0000-0001-7606-5060
page: 4

CASE PRESENTATION

A 43-year-old woman was referred to the department of Diabetology for assessment of glucose tolerance. She had a history of gestational diabetes during her first pregnancy at the age of 26 with fasting glucose concentrations of 7 to 8 mmol/l. She did not receive insulin therapy during pregnancy and her glucose tolerance was not reassessed after delivery nor during her second pregnancy. Both babies weighted below 4 kg at birth – 3650 g and 3000 g, respectively, but the first delivery was 2 weeks preterm. In the following years her fasting glucose was constantly within the range of 6.5 to 8.2 mmol/l and metformin therapy was initiated. The patient had concomitant autoimmune thyroiditis and beta thalassemia. The family history was abundant - her father had elevated fasting glucose values around 8 mmol/l though he was never treated for hyperglycemia, her mother had Grave’s disease and vitiligo, one of the patient’s sons, a first cousin, and a nephew all had beta thalassemia. Physical examination revealed no abnormalities, the patient had a BMI of 19.5 kg/m2, waist circumference of 71 cm and blood pressure of 120/70 mmHg. Clinical investigation - Assessment of glucose tolerance and insulin resistance - oral glucose tolerance test ( OGTT) was performed after discontinuation of metformin and revealed a state of prediabetes - impaired fasting glucose. Fasting insulin was low normal and calculated HOMA IR was within range. (Table 1) HbA1c was 5.2% in the setting of hemoglobin concentration of 126 G/l. - Assessment of immunologic markers - islet cell antibodies - anti-GAD 65-Ab, anti-IA 2-Ab and anti-ZnT8-Ab, were negative. - Assessment of insulin secretion - intravenous glucose tolerance test (IVGTT) demonstrated preserved endogenous insulin secretion. (Table 2) - Assessment of glycemic control - continuous glucose monitoring (CGM) (FreeStyle Libre) showed good glycemic control and no need of pharmacologic therapy at this stage. (Figure 1) - Other - serum lipids and TSH were within normal range. Genetic testing - NGS sequencing Based on clinical suspicion of a specific monogenic form of diabetes running in her family the patient was referred for genetic testing. Genomic DNA was extracted from a blood sample taken after informed consent was signed. A custom panel was used for library preparation that included the exons and exon-intron boundaries of 99 genes associated with different syndromic and nonsyndromic causes of monogenic diabetes. All 14 genes implicated in the different subtypes of MODY were included in the gene panel. Next-generation sequencing (NGS) was performed on an Illumina MiSeq platform. - NGS data analysis and variant classification MiSeq reporter software was used for standard bioinformatic analysis. The generated VCF file was annotated using wANNOVAR software [6]. After common polymorphisms were filtered out, all remaining rare variants were classified according to the ACMG guidelines [7]. The patient was found to be a carrier of a heterozygous pathogenic variant in GCK (c.184G>A).

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