Wu Kan, Wang Hongyang, Guan Jing, Lan Lan, Zhao Cui, Zhang Mengqian, Wang Dayong, Wang Qiuju
Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, 100853, China.
Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, 100853, China.
Int J Pediatr Otorhinolaryngol. 2020 Jun;133:109947. doi: 10.1016/j.ijporl.2020.109947. Epub 2020 Feb 13.
To determine the genetic cause of non-syndromic autosomal dominant deafness segregating in a Chinese Auditory neuropathy (AN) family.
AN is a genetically related rare disease characterized by sensorineural hearing loss and retention of hair cell function. Diaphanous Homolog 1 (DIAPH1) is the causative gene of DFNA1. To date, no evidence has been detected to reveal the connection between gene DIAPH1 and AN.
Audiological and imageological examinations, genome-wide linkage analysis, and whole exome sequencing (WES) were carried out on the family members.
In the 13-member branch of the family, 4 patients with preserved otoacoustic emission or cochlear microphonic and abnormal auditory brainstem responses were diagnosed with AN. Linkage analysis detected an interval with a LOD (log odds) score >4 on chr5:138.845-149.509 cM. Using WES we identified a novel frameshift variant c.3551_3552del (p.Glu1184AlafsTer11) in exon 26 of DIAPH1 located in the linkage region. The variant was co-segregated with hearing impairment phenotype in the family except 4 members below the average age of onset. We have found sufficient evidence conforming with the American College of Medical Genetics and Genomics Guideline to consider c.3551_3552del as the genetic cause of the family patients.
It is the first report to expand DIAPH1-related phenotypic spectrum to include AN. Our findings could facilitate the clinical diagnosis and genetic counselling for AN, especially for those with DIAPH1 variants.
确定一个中国听觉神经病（AN）家系中分离的非综合征性常染色体显性耳聋的遗传原因。
AN是一种与遗传相关的罕见疾病，其特征为感音神经性听力损失和毛细胞功能保留。透明同系物1（DIAPH1）是DFNA1的致病基因。迄今为止，尚未发现证据揭示基因DIAPH1与AN之间的联系。
对该家系成员进行了听力学和影像学检查、全基因组连锁分析以及全外显子组测序（WES）。
在该家系的13名成员分支中，4名耳声发射或耳蜗微音电位正常但听觉脑干反应异常的患者被诊断为AN。连锁分析在5号染色体138.845 - 149.509 cM处检测到一个LOD（对数优势）得分>4的区间。通过WES，我们在位于连锁区域的DIAPH1基因第26外显子中鉴定出一个新的移码变异c.3551_3552del（p.Glu1184AlafsTer11）。除4名低于平均发病年龄的成员外，该变异与家系中的听力障碍表型共分离。我们已找到符合美国医学遗传学与基因组学学会指南的充分证据，将c.3551_3552del视为该家系患者的遗传病因。
这是首次将DIAPH1相关表型谱扩展至包括AN的报告。我们的发现有助于AN的临床诊断和遗传咨询，特别是对于那些携带DIAPH1变异的患者。
