Chaussenot A, Rouzier C, Quere M, Plutino M, Ait-El-Mkadem S, Bannwarth S, Barth M, Dollfus H, Charles P, Nicolino M, Chabrol B, Vialettes B, Paquis-Flucklinger V
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.
Clin Genet. 2015 May;87(5):430-9. doi: 10.1111/cge.12437. Epub 2014 Aug 6.
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.
WFS1基因突变导致以青少年发病的糖尿病和视神经萎缩为特征的沃夫勒姆综合征（WS），以及低频感音神经性听力损失（LFSNHL）。我们的目的是分析96例与WFS1相关疾病的法国患者队列，以便（i）用37名新确诊的患者更新临床和分子数据，（ii）描述不常见的表型，以及（iii）明确WFS1中大规模重排的频率。我们对13例仅携带一个杂合变异的患者进行了定量聚合酶链反应（PCR），以鉴定WFS1中的大规模重排。在37名新患者中，15名携带15个新的有害推定突变，包括一个17444个碱基对的大缺失。对该队列的分析揭示了意外的表型，包括（i）13.8%可能为常染色体隐性遗传的患者出现迟发性症状；（ii）两名患有隐性视神经萎缩但无糖尿病的兄弟姐妹，以及（iii）来自四个家庭的六名患者患有显性遗传性耳聋和视神经萎缩。我们强调了与WFS1相关疾病谱的不断扩大，并表明，即使大缺失是罕见事件，但在测序后仅携带一个WFS1突变的典型WS患者中仍需进行检测。
