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Abstract：
OBJECTIVE: To determine the spectrum and frequency of disease-causing variants in patients with non-syndromic hearing loss (NSHL) and to investigate the diagnostic yield of the applied genetic methods.
METHODS: The study enrolled 306 unrelated patients with childhood-onset, mild-to-profound NSHL referred to Children\'s Hospital Zagreb for genetic testing between March 2006 and October 2023. The GJB2 variants were analyzed with the multiplex ligation-dependent probe amplification method and Sanger sequencing of the coding region of the GJB2 gene. In 21 patients negative for GJB2 biallelic variants, clinical exome sequencing (CES) was performed.
RESULTS: Among 234 disease-associated GJB2 alleles detected, 19 were clinically relevant, of which 18 were reported as pathogenic/likely pathogenic. The c.35delG variant accounted for 73.5% of the mutated alleles. More than half of the patients with biallelic GJB2 variants (64/110, 58.2%) were 35delG homozygotes. Seventeen non-GJB2 variants were found in 10 genes (TECTA, NOG, SLC26A4, PCDH15, TMPRSS3, USH2A, GATA3, MYO15A, SOX10, COL2A1) in 11 participants, and 5 variants (in TECTA, NOG, PCDH15, and SOX10) were novel (29.4%).
CONCLUSIONS: We were able to elucidate the genetic cause of hearing loss in 121 patients, with an overall diagnostic rate of 39.5%. The c.35delG was the most common variant. CES allowed us to diagnose almost half of the patients with HL; to distinguish NSHL from the syndromic form of HL in cases where the phenotype was unclear or where symptoms were absent from an early age; and to discover novel variants.
METHODS: The study enrolled 306 unrelated patients with childhood-onset, mild-to-profound NSHL referred to Children\'s Hospital Zagreb for genetic testing between March 2006 and October 2023. The GJB2 variants were analyzed with the multiplex ligation-dependent probe amplification method and Sanger sequencing of the coding region of the GJB2 gene. In 21 patients negative for GJB2 biallelic variants, clinical exome sequencing (CES) was performed.
RESULTS: Among 234 disease-associated GJB2 alleles detected, 19 were clinically relevant, of which 18 were reported as pathogenic/likely pathogenic. The c.35delG variant accounted for 73.5% of the mutated alleles. More than half of the patients with biallelic GJB2 variants (64/110, 58.2%) were 35delG homozygotes. Seventeen non-GJB2 variants were found in 10 genes (TECTA, NOG, SLC26A4, PCDH15, TMPRSS3, USH2A, GATA3, MYO15A, SOX10, COL2A1) in 11 participants, and 5 variants (in TECTA, NOG, PCDH15, and SOX10) were novel (29.4%).
CONCLUSIONS: We were able to elucidate the genetic cause of hearing loss in 121 patients, with an overall diagnostic rate of 39.5%. The c.35delG was the most common variant. CES allowed us to diagnose almost half of the patients with HL; to distinguish NSHL from the syndromic form of HL in cases where the phenotype was unclear or where symptoms were absent from an early age; and to discover novel variants.
摘要：
目的：确定非综合征性听力损失（NSHL）患者中致病变异的频谱和频率，并研究应用的遗传方法的诊断率。
方法：该研究招募了306名儿童期发病的无关患者，在2006年3月至2023年10月之间，轻度至深度的NSHL转诊至萨格勒布儿童医院进行基因检测。用多重连接依赖性探针扩增方法和GJB2基因编码区的Sanger测序分析GJB2变体。在21例GJB2双等位基因变异阴性的患者中，进行临床外显子组测序(CES).
结果：在检测到的234个疾病相关GJB2等位基因中，19是临床相关的，其中18例报告为致病性/可能致病性。c.35delG变体占突变等位基因的73.5%。超过一半的具有双等位基因GJB2变体的患者(64/110,58.2%)是35delG纯合子。在10个基因中发现了17种非GJB2变体(TECTA，NOG,SLC26A4,PCDH15,TMPRSS3,USH2A,GATA3,MYO15A,SOX10，COL2A1）在11名参与者中，和5个变体(在TECTA中，NOG,PCDH15和SOX10)是新的(29.4%)。
结论：我们能够阐明121例患者听力损失的遗传原因，总体诊断率为39.5%。c.35delG是最常见的变体。CES使我们能够诊断几乎一半的HL患者；在表型不明确或从小就没有症状的情况下，将NSHL与HL的综合征形式区分开来；并发现新的变体。
方法：该研究招募了306名儿童期发病的无关患者，在2006年3月至2023年10月之间，轻度至深度的NSHL转诊至萨格勒布儿童医院进行基因检测。用多重连接依赖性探针扩增方法和GJB2基因编码区的Sanger测序分析GJB2变体。在21例GJB2双等位基因变异阴性的患者中，进行临床外显子组测序(CES).
结果：在检测到的234个疾病相关GJB2等位基因中，19是临床相关的，其中18例报告为致病性/可能致病性。c.35delG变体占突变等位基因的73.5%。超过一半的具有双等位基因GJB2变体的患者(64/110,58.2%)是35delG纯合子。在10个基因中发现了17种非GJB2变体(TECTA，NOG,SLC26A4,PCDH15,TMPRSS3,USH2A,GATA3,MYO15A,SOX10，COL2A1）在11名参与者中，和5个变体(在TECTA中，NOG,PCDH15和SOX10)是新的(29.4%)。
结论：我们能够阐明121例患者听力损失的遗传原因，总体诊断率为39.5%。c.35delG是最常见的变体。CES使我们能够诊断几乎一半的HL患者；在表型不明确或从小就没有症状的情况下，将NSHL与HL的综合征形式区分开来；并发现新的变体。
