Abstract 114: WFS1 gene associated diabetes phenotypes and identification of a novel founder mutation in Southern India

Background: Wolfram Syndrome (WFS) is a rare, autosomal recessive, progressive disorder characterized by childhood-onset diabetes mellitus (DM), diabetes insipidus, optic atrophy, and sensorineural hearing loss (DIDMOAD). The confirmed early diagnosis of WFS is challenging due to the progressive nature of the disease and WFS1 rare heterozygous variants reported in young-onset DM, the need for comprehensive genetic screening for the early diagnosis of WFS and to characterize the phenotypic spectrum associated with diabetes mellitus. Aims and Objectives: To screen a comprehensive panel of seventeen monogenic diabetes genes in patients with DM, with a clinical suspicion of WFS/non autoimmune T1DM/Young onset DM patients who were tested negative for a MODY panel. Results: Fourteen patients positive for WFS1 variants identified by Next-generation sequencing. Ten patients were positive for homozygous WFS1 mutations, which includes a novel founder mutation WFS1 (NM_006005.3): c.1107_1108insA (p.Ala370SerfsTer173) in three families from south India. We have also identified rare heterozygous WFS1 variants in four patients with young onset diabetes. Conclusion: These findings project the need for NGS-based parallel multigene testing for early diagnosis of WFS and to identify heterozygous WFS1 variants implicated in young onset DM.