LAUSR

Abstract ABCC8 encodes the SUR-1 subunit of the ATP-sensitive potassium (K-ATP) channel on beta cells. Mutations in this gene are associated with K-ATP channel gain of function (diabetes mellitus) and loss of function (hyperinsulinism). We describe a family with a heterozygous variant of uncertain significance (VUS) in the ABCC8 gene that may be associated with both diabetes mellitus and congenital hyperinsulinism. A macrosomic boy (birth weight 3.86kg; >99th centile) was born to a mother with type 2 diabetes. On day 7 of life he was diagnosed with hyperinsulinism based on an insulin of 46.1mIU/L (2.6-24.9) and glucose of 2.2mmol/L. He responded to diazoxide and his hypoglycaemia appeared to resolve by 6 months old. The boy had an older half-sister who was also macrosomic at birth (>99th centile) and had diazoxide-responsive congenital hyperinsulinism which required treatment until two years of age. He also had an older brother who was stillborn with severe macrosomia at 36 weeks weighing 5.7kg (well above 99th centile). There was a family history of stillbirth of very macrosomic babies in five cases across two generations from three mothers. The boy’s mother was macrosomic and possibly hypoglycaemic as a neonate. She developed gestational diabetes in all of her pregnancies and diabetes at age 30 years. There is also adult-onset diabetes mellitus in the boy’s maternal grandmother, maternal great-aunt and maternal great-grandmother (diagnosed in the fourth or fifth decade). The cases of hyperinsulinism/foetal macrosomia and adult-onset diabetes follow an autosomal dominant pattern. Hyperinsulinism gene panel analysis revealed a heterozygous missense mutation in the ABCC8 gene (Ala1457Thr) in the boy, which was then found in his half-sister and mother. The VUS is in a highly conserved region of the SUR1 subunit and in-silico analysis tools suggest a deleterious effect. It has been reported in cases of hyperinsulinism (MacMullen 2011) and adult-onset diabetes mellitus (Ovsyannikova 2016), but never within the same pedigree. Genetic testing of other affected and unaffected family members is underway. This case suggests that a single heterozygous mutation (Ala1457Thr) in ABCC8, currently listed as VUS, may be responsible for both loss of function (hyperinsulinism) and gain of function (diabetes mellitus) of the K-ATP channel within a single pedigree. References MacMullen, C, Zhou, Q, Snider, E, Tewson, P, Becker, S, Aziz, A, Stanley, C. (2011). Diazoxide-Unresponsive Congenital Hyperinsulinism in Children With Dominant Mutations of the β-Cell Sulfonylurea Receptor SUR1. Diabetes, 60(6), 1797-1804. doi:10.2337/db10-1631 Ovsyannikova, A, Rymar, O, Shakhtshneider, E, Klimontov, V, Koroleva, E, Myakina, N, & Voevoda, M (2016). ABCC8 Related Maturity Onset Diabetes of the Young (MODY12) Clinical Features and Treatment Perspective. Diabetes Therapy, 7(3), 591-600. doi:10.1007/s13300-016-0192-9