A Novel Compound Heterozygous Mutation in the WFS1 Gene (C.1997 G>A and C.2113_2114 ins T) Causes wolfram Syndrome: A Case Report

Abstract Background:Wolfram syndrome (WS) is a rare autosomal recessive disorder associated with early-onset diabetes mellitus (DM), diabetes insipidus (DI), optic atrophy (OA) and hearing impairment. Most patients with WS have mutations in the WFS1 gene, which encodes wolframin. This case report describes a patient with a novel heterozygous mutation of WFS1.Case Presentation:The proband was a 27-year-old Chinese male with WS who had developed DM at the age of 2 years, DI in the first decade, OA, neurogenic bladder and urinary tract infections in the second decade, and neurological abnormalities in later life. Magnetic resonance imaging suggested superior sagittal sinus enlargement and atrophy of the medulla and pons. Sequencing showed that the proband’s asymptomatic parents were both carriers: the father carried a heterozygous c.1997G>A mutation that creates a premature stop at codon 666 (W666X) and that the proband’s asymptomatic mother carried a heterozygous c.2113_2114insT mutation that generates a frameshift downstream to codon 705 (K705Ifs*7) and leads to a stop at codon 711. The proband had both the above C-terminal mutations, resulting in the substitution of N-glycosylation sitesthat are associated with the stability of wolframin.Conclusion:We have identified a novel compound heterozygous mutation of WFS1 that is associated with WS. Our findings may facilitate future screening of WS carriers.