1463-P: Heterozygous Variant in NFKB1 Presenting with Autoantibody-Negative (AbNeg) Insulin-Dependent Diabetes (IDDM)

Abstract

Due to its uncertain etiology and clinical management, AbNeg IDDM is a phenotype of interest for the NIH-funded Rare and Atypical Diabetes Network (RADIANT), which aims to identify and characterize people with unknown forms of diabetes (DM). We report a case of childhood-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. A 17-year-old female presented with DM at age 7 with A1c 10.8%; random C-peptide 0.21 ng/ml; no diabetic ketoacidosis; negative GAD65, insulin, IA-2 and ZnT8 Ab; normal BMI%ile; no signs of insulin resistance; and negative genetic testing for monogenic DM. She has required continuous insulin therapy. Past medical history: IgA deficiency, vitamin D deficiency, orthostatic intolerance, neurocardiogenic pre-syncope and chronic migraine. Family history: Autoimmune adult-onset DM and hypothyroidism in mother, frequent upper respiratory infections in sisters, Addison’s disease in maternal grandfather, hemochromatosis in paternal grandmother and pericarditis at age 30 in paternal grandfather. Physical exam: Unremarkable. RADIANT Labs: Undetectable serum C-peptide. Negative Ab. Whole genome sequencing: Heterozygous likely pathogenic variant in NFKB1 impacting the canonical splice acceptor sequence (NM_003998.4:c.1753-1G>C). This is a case of youth-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. Heterozygous loss-of-function variants in NFKB1 are associated with Common Variable Immunodeficiency (CVID) type 12 (OMIM #616576), characterized by incomplete penetrance and variable expressivity of immunodeficiency and autoimmunity, including features of IDDM. Immune dysregulation may explain lack of classic Ab. There are no prior reports of CVID first ascertained through a DM phenotype. Thus, this case represents a phenotype expansion of NFKB1-associated disease, and contributes to our understanding of the heterogeneity of AbNeg IDDM. Genetic testing of first-degree relatives is underway. Disclosure M.J.Redondo: None. A.Balasubramanyam: None. P.Liu: Other Relationship; Baylor Genetics. A.N.Alkanaq: None. M.Tosur: Advisory Panel; Provention Bio, Inc. N.Ram: None. R.J.Kreienkamp: None. E.A.Oral: Advisory Panel; Amryt Pharma Plc, Regeneron, Rejuvenate Bio, Third Rock Ventures, Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals, Regeneron, Other Relationship; Amryt Pharma Plc, Research Support; Amryt Pharma Plc, Novo Nordisk, Fractyl Health, Inc., Ionis Pharmaceuticals, Regeneron, GI Dynamics, Rejuvenate Bio. C.Pihoker: None. J.Posey: None. Funding National Institutes of Health (U54DK118638)