ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 P620 | DOI: 10.1530/endoabs.63.P620

Next generation sequencing reveals ABCC8 (MODY 12) variants in two families with diabetes mellitus (DM)

Athina Markou1, Amalia Sertedaki2, Elizabeth Tatsi2, George Piaditis1, Theodora Kounadi1 & Christina Kanaka-Gantenbein2

1Endocrinology Department, General Hospital of Athens ‘G. Gennimatas’, Athens, Greece; 2Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens School of Medicine, ‘Agia Sophia’ Children’s Hospital, Athens, Greece.

Introduction: Maturity Onset Diabetes of the Young (MODY) constitutes a genetically and clinically heterogeneous type of Monogenic Diabetes (MD). It is characterized by autosomal dominant inheritance, early onset diabetes, defect in the β-cell insulin secretion, positive family history, absence of diabetic ketoacidosis, auto-antibodies and insulin resistance. To date, 14 different MODY subtypes have been reported each one with distinct genetic etiology, however MODY patients are frequently misdiagnosed as DT 1 or 2. ABCC8 gene variants are associated with neonatal diabetes, hyperinsulinism and MODY.

Aim: To identify the molecular defect of two families suspected for MODY employing a Next Generation Sequencing (NGS) Targeted Gene Panel for 7 MODY genes (GCK, HNF1A, HNF4A, HNF1B, INS, ABCC8,KCNJ11).

Methods-Results: Family A: A 24 year old man (BMI=23) presented at the emergency department with hyperglycaemia (glucose=365 mg/dl, HbA1c=11.9%), without ketoacidosis and negative anti GAD/ICA antibodies. He was treated with insulin and metformin. Insulin was decreased and discontinued within a month. While on metformin and appropriate diet his HbA1c was 5.5%, but later increased at 7.7%. Father: DM on tablets since the age of 48. Mother: impaired glucose tolerance (IGT). Maternal grandfather: insulin-treated DM since the age of 45. Genetic analysis of patient’s DNA revealed that the patient and his mother were heterozygotes for the p.Glu1206Lys variant of the ABCC8 gene. After switching him to gliclazide and adding metformin, his HbA1c was 5.6% with stable glucose levels.

Family B: Son 1(49 years old): DM at 32 with glucose>300 mg/dl, HbA1c=10.6% and BMI=29. His was treated with metformin±pioglitazone±sitagliptin with 5.5% Son 2 (39 years old): DM at 25 with HbA1c=7.9% and BMI of 24. He was treated with metformin±saxagliptin and 9 years later basal insulin was added. His HbA1c is 5.6% and BMI=27. Both sons had no diabetic complications, anti GAD/ICA antibodies nor ketoacidosis. Father: DM at 46, on metformin±sulfonylurea±sitagliptin, BMI=26.5, HbA1c=6.3%. Mother: IGT. Genetic analysis of the family revealed that the two sons and their father were heterozygotes for the p.Ser1386Phe variant of the ABCC8 gene.

Conclusions: ABCC8 (MODY 12) patients exhibit genetic heterogeneity, even within the same family, ranging from impaired glucose tolerance to insulin treated diabetes. Genetic testing for the recognition of MODY subtype is of outmost importance for diagnosis, prognosis, treatment and family counseling.

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