title: Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders.
abstract: WFS1 mutations are responsible for Wolfram syndrome (WS) characterized by juvenile-onset diabetes mellitus and optic atrophy, and for low-frequency sensorineural hearing loss (LFSNHL). Our aim was to analyze the French cohort of 96 patients with WFS1-related disorders in order (i) to update clinical and molecular data with 37 novel affected individuals, (ii) to describe uncommon phenotypes and, (iii) to precise the frequency of large-scale rearrangements in WFS1. We performed quantitative polymerase chain reaction (PCR) in 13 patients, carrying only one heterozygous variant, to identify large-scale rearrangements in WFS1. Among the 37 novel patients, 15 carried 15 novel deleterious putative mutations, including one large deletion of 17,444 base pairs. The analysis of the cohort revealed unexpected phenotypes including (i) late-onset symptoms in 13.8% of patients with a probable autosomal recessive transmission; (ii) two siblings with recessive optic atrophy without diabetes mellitus and, (iii) six patients from four families with dominantly-inherited deafness and optic atrophy. We highlight the expanding spectrum of WFS1-related disorders and we show that, even if large deletions are rare events, they have to be searched in patients with classical WS carrying only one WFS1 mutation after sequencing.
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice, France; IRCAN UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice, France.
authors.forename: A
authors.initials: A
authors.lastname: Chaussenot
authors.forename: C
authors.initials: C
authors.lastname: Rouzier
authors.forename: M
authors.initials: M
authors.lastname: Quere
authors.forename: M
authors.initials: M
authors.lastname: Plutino
authors.forename: S
authors.initials: S
authors.lastname: Ait-El-Mkadem
authors.forename: S
authors.initials: S
authors.lastname: Bannwarth
authors.forename: M
authors.initials: M
authors.lastname: Barth
authors.forename: H
authors.initials: H
authors.lastname: Dollfus
authors.forename: P
authors.initials: P
authors.lastname: Charles
authors.forename: M
authors.initials: M
authors.lastname: Nicolino
authors.forename: B
authors.initials: B
authors.lastname: Chabrol
authors.forename: B
authors.initials: B
authors.lastname: Vialettes
authors.forename: V
authors.initials: V
authors.lastname: Paquis-Flucklinger
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D015331:Cohort Studies; D005190:Family; D005260:Female; D005602:France; D005799:Genes, Dominant; D005808:Genes, Recessive; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D014929:Wolfram Syndrome / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult
chemical_list: C523851:CISD2 protein, human; D008565:Membrane Proteins; C114987:wolframin protein
keywords: WFS1; Wolfram syndrome; large-scale rearrangements; uncommon phenotype