Genetic and phenotypic analysis of MYO15A rare variants associated with autosomal recessive hearing loss
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摘要: 目的 分析 MYO15A 基因突变导致的常染色体隐性遗传性耳聋的表型及基因型特点, 为基因诊断提供依据, 为患者及家庭提供遗传咨询。方法 对上海交通大学医学院附属第九人民医院经二代测序检测诊断为 MYO15A 基因突变导致耳聋的2例散发病例进行基因的突变分析, 并在家系内行Sanger测序验证分析。结合临床资料, 依据美国医学遗传学和基因组学会(American College of Medical Genetics and Genomics, ACMG)变异分类指南对突变位点进行致病性判定。结果 2个散发耳聋家系的先证者表型分别为双侧重度听力损失与完全听力损失。鉴定了 MYO15A 基因4个变异, 其中致病变异1个, 可能致病变异2个, 临床意义未明的剪切位点变异1个。患者Ⅰ携带的c.3524dup (p.Ser1176Valfs*14)变异为已报道致病变异; 携带的c.10082+3G>A剪切位点变异, 根据ACMG指南判定为临床意义未明。患者双侧佩戴助听器后, 右耳平均听阈值37.50 dB, 左耳平均听阈值33.75 dB。患者Ⅱ携带c.7441_7442del (p.Leu2481Glufs*86)、c.10250_10252del (p.Ser3417del), 根据ACMG指南判定为可能致病的。患者右侧人工耳蜗植入术后8年, 听觉行为分级-Ⅱ(categorical auditory performance, CAP-Ⅱ)9分, 言语可懂度分级(speech intelligibility rating, SIR)5分。结论 本研究新发现的 MYO15A 基因罕见的c.7441_7442del突变与剪切位点突变c.10082+3G>A与常染色体隐性遗传性耳聋密切相关, 丰富了 MYO15A 基因突变谱, 为遗传性耳聋的遗传咨询提供依据。其次剪切位点致病性评估的应用为相关位点的分类提供参考。Abstract: Objective To analyze the phenotype and genotype characteristics of autosomal recessive hearing loss caused by MYO15A gene variants, and to provide genetic diagnosis and genetic counseling for patients and their families.Methods Identification of MYO15A gene variants by next generation sequencing in two sporadic cases of hearing loss at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The sequence variants were verified by Sanger sequencing.The pathogenicity of these variants was determined according to the American College of Medical Genetics and Genomics(ACMG) variant classification guidelines, in conjuction with clinical data.Results The probands of the two families have bilateral, severe or complete hearing loss.Four variants of MYO15A were identified, including one pathogenic variant that has been reported, two likely pathogenic variants, and one splicing variant of uncertain significance. Patient I carries c. 3524dupA(p. Ser1176Valfs*14), a reported pathogenic variant, and a splicing variant c. 10082+3G>A of uncertain significance according to the ACMG guidelines. Patient I was treated with bilateral hearing aids with satisfactory effect, demonstrated average hearing thresholds of 37.5 dB in the right ear and 33.75 dB in the left ear. Patient Ⅱ carries c. 7441_7442del(p. Leu2481Glufs*86) and c. 10250_10252del(p. Ser3417del), a pair of as likely pathogenic variants according to the ACMG guidelines. Patient Ⅱ, who underwent right cochlear implantation eight years ago, achieved scores of 9 on the Categorical Auditory Performance-Ⅱ(CAP-Ⅱ) and 5 on the Speech Intelligibility Rating(SIR).Conclusion This study's discovery of the rare c. 7441_7442del variant and the splicing variant c. 10082+3G>A in the MYO15A gene is closely associated with autosomal recessive hearing loss, expanding the MYO15A variant spectrum. Additionally, the pathogenicity assessment of the splicing variant facilitates classification of splicing variations.
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Key words:
- Hereditary hearing loss tacilitates /
- MYO15A /
- Genotype /
- Phenotype /
- Genetic counseling
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表 1 本研究 MYO15A 基因变异位点致病性分析
RS编号 染色体位置 核苷酸氨基酸 转录本外显子 病例编号 听力分级 变异类型 MAF ACMG
分级标准ACMG
分类Clivar DVD SpliceAI DS(DP)* SpliceAI-visual RS(DP) rs766187994 chr17：18025638 c.3524 dup
(p.Ser1176 Valfs*14)NM_016239.4；exon2 Ⅰ 重度 移码突变 0.000142
(gnomAD_Exomes in total)PVS1，PM2，PM3 P P/LP — — — rs1555548136 chr17：18071040 c.10082+3G>A NM_016239.4；exon 61 Ⅰ 重度 剪切突变 0.00011
(3/28258，14KJPN)PM2，PM3 VUS — — AG=0.00 (-37) AL=0.00 (-5) DG=0.01 (-3) DL=0.17 (-5) Ref：D=-0.992(-3)
D=0.18 (-5)
Var：D=-0.998(-3)
D=0.015 (-5)rs1213371923 chr17：18054195-18054196 c.7441_7442 del(p.Leu2481 Glufs*86) NM_016239.4；exon 38 Ⅱ 完全听力损失 移码突变 0.000014
(gnomAD_Exomes in total)PVS1，PM2 LP — — — — rs760069953 chr17：18075504 -18075506 c.10250_10252 del(p.Ser3417 del) NM_016239.4；exon 64 Ⅱ 完全听力损失 整码突变 0.000028
(GnomAD_exome in total)PM2，PM3，PM4 LP P/LP/VUS — — — 
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