MYO15A基因突变是全球公认的常染色体隐性遗传非综合征性感觉神经性听力损失(NSHL)的原因。这里,我们研究了MYO15A变异体在中国NSHL病例队列中的作用和基因型-表型相关性.
在2263例中国NSHL病例中,81例具有MYO15A变异的病例,谁接受了下一代测序(NGS),参加了这项研究。我们调查了MYO15A变异与严重程度的关联,听力损失的进展和发病年龄,以及将其与以前不同国籍的报告进行比较。根据截断变异的数量分为两组:2个截断,1个截断和1个非截断,2个非截短变体,并比较各组HL的严重程度。
MYO15A占所有NSHL病例的3.58%(81/2263)。我们分析了81例MYO15A相关的NSHL病例,其中73人患有先天性双侧,对称性或重度至深度听力损失(HL),然而,其中2人有一个后语言,不对称,轻度或中度HL。在所有MYO15A结构域中鉴定出102个变体,其中76.47%(78/102)是小说。最常见的检测变异类型是错义(44/102,43.14%),其次是移码(27/102,26.47%),废话(14/102,13.72%),剪接位点(10/102,9.80%),帧(4/102,3.92%),非编码(2/102,1.96%)和同义(1/102,0.98%)。12例检出最多复发变异c.10245_10247delCTC。我们观察到MYO15A变体,位于其N端,电机和FERM域,导致部分耳聋,低频残余听力较好。有34例双等位基因截短变异,37例单等位基因截短变异,13例具有双等位基因非截短变体。双等位基因非截短变体组的病例数最少(12/81),他们中的大多数(10/12)患有深奥的NSHL。
MYO15A是中国NSHL的主要基因。MYO15A变异的病例大多表现为早发性,对称,严重到严重的听力损失。迄今为止,这项研究最大的重点是评估MYO15A基因变体之间的基因型-表型相关性及其在NSHL结果中的意义。双等位基因非截短的MYO15A变体通常导致严重的HL,具有一个或两个截短的MYO15A变体的病例倾向于增加HL的风险。然而,在这些病例中,我们需要进一步调查以阐明听力损失的严重程度和进展率以及检测到的MYO15A变异的原因.
Mutations in the
MYO15A gene are a widely recognized cause of autosomal recessive non-syndromic sensorineural hearing loss (NSHL) globally. Here, we examined the role and the genotype-phenotype correlation of MYO15A variants in a cohort of Chinese NSHL cases.
Eighty-one cases with evidenced MYO15A variants from the 2263 Chinese NSHL cases, who underwent next-generation sequencing (NGS), were enrolled in the study. We investigated the association of
MYO15A variants with the severity, progression and age of onset of hearing loss, as well as compared it to the previous reports in different nationalities. The cases were divided into groups according to the number of truncating variants: 2 truncating, 1 truncating and 1 non-truncating, 2 non-truncating variants, and compared the severity of HL among the groups.
MYO15A accounted for 3.58% (81/2263) of all NSHL cases. We analyzed 81 MYO15A-related NSHL cases, 73 of whom were with congenital bilateral, symmetric or severe-to-profound hearing loss (HL), however, 2 of them had a postlingual, asymmetric, mild or moderate HL. There were 102 variants identified in all MYO15A structural domains, 76.47% (78/102) of whom were novel. The most common types of detected variants were missense (44/102, 43.14%), followed by frameshift (27/102, 26.47%), nonsense (14/102, 13.72%), splice site (10/102, 9.80%), in frame (4/102, 3.92%), non-coding (2/102, 1.96%) and synonymous (1/102, 0.98%). The most recurrent variant c.10245_10247delCTC was detected in 12 cases. We observed that the MYO15A variants, located in its N-terminal, motor and FERM domains, led to partial deafness with better residual hearing at low frequencies. There were 34 cases with biallelic truncating variants, 37 cases with monoallelic truncating variants, and 13 cases with biallelic non-truncating variants. The biallelic non-truncating variants group had the least number of cases (12/81), and most of them (10/12) were with profound NSHL.
MYO15A is a major gene responsible for NSHL in China. Cases with MYO15A variants mostly showed early-onset, symmetric, severe-to-profound hearing loss. This study is by far the largest focused on the evaluation of the genotype-phenotype correlations among the variants in the MYO15A gene and its implication in the outcome of NSHL. The biallelic non-truncating MYO15A variants commonly caused profound HL, and the cases with one or two truncating
MYO15A variants tended to increase the risk of HL. Nevertheless, further investigations are needed to clarify the causes for the variable severities and progression rates of hearing loss and the detected MYO15A variants in these cases.