1475-P: Novel Mutations in the Wolframin Gene with Diabetes—A Case Series of a Potential Addition to the Monogenic Diabetes Profile

Abstract

Monogenic DM (MGDM) is a heterogeneous group of disorders caused by single gene mutations resulting in variable clinical phenotypes of diabetes mellitus (DM). While maturity onset diabetes of the young (MODY) remains the most known group, it is now recognized that there are other single gene defects associated with DM. Current MODY classification details 14 distinct genetic types which are mostly autosomal dominant (AD). We present a case series of 4 African-American (AA) men with novel mutations of the Wolframin (WS1) gene and type 2 DM (T2DM) phenotype. Patient 1 is a 54-yr-old AA man with presumed T2DM. Given his lack of family DM history, short DM duration, late onset and rapid renal functional decline, the possibility of atypical DM was considered. Genetic testing showed a heterozygous mutation of the WFS1 (wolframin gene); c.169 G>A, p.Ala57Thr. He had no other features of Wolfram’s syndrome; DIDMOAD (diabetes insipidus, DM, optic atrophy + deafness). Pts 2-4 are all family members. Pt 2 is a 65-yr-old AA man with new onset DKA and presumed T2DM. Given his initial DKA presentation, non-obese phenotype and absent family DM history, full phenotyping was done and genetic testing revealed a heterozygous mutation of the WFS1 gene; c.2385 G>C, p.Glu795Asp. He had no other features of DIDMOAD. Neither of his parents had DM and nor does his wife. He has 3 children (two sons and a daughter). Both sons (Pts 3-4), aged 41 and 36 yrs, have DM and both have the same WFS1 mutation. Both sons were diagnosed with DM before their father. The familial distribution suggests possible AD transmission. WFS1 mutations have a broad spectrum of phenotypes and inheritance patterns. Our case series with unique WFS1 mutations suggests a possible MGDM syndrome in subjects with heterozygous WFS1 mutations without DIDMOAD. Further functional analyses of WFS1 mutations associated with DM without DIDMOAD are needed to better understand their DM pathophysiology and inform best management strategies. Disclosure Z.Yin: None. A.A.Noor: None. K.G.Romo: None. S.Bhamre: None. M.Gabriel: None. T.Pulisetty: None. S.Shu: None. G.I.Uwaifo: None.