The updates of the ACMG variant interpretation guidelines affect the pathogenicity determination of OTOF gene variations in patients with auditory neuropathy
10.3760/cma.j.cn115330-20231129-00254
- VernacularTitle:ACMG变异解读指南更新对听神经病患者 OTOF基因变异致病性判定的影响
- Author:
Kaili WU
1
;
Jin LI
;
Hongyang WANG
;
Qiuju WANG
Author Information
1. 中国人民解放军总医院第六医学中心耳鼻咽喉头颈外科医学部耳鼻咽喉内科，北京 100048；听觉与平衡觉全国重点实验室 国家耳鼻咽喉疾病临床医学研究中心，北京 100853
- Keywords:
Auditory neuropathy;
Gene mutation;
OTOF gene;
Pathogenicity
- From:
Chinese Journal of Otorhinolaryngology Head and Neck Surgery
2024;59(5):455-463
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To compare the differences between the variation interpretation standards and guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 (The 2015ACMG/AMP guideline) and the Deafness Specialist Group of the Clinical Genome Resource (ClinGen) in 2018 for hereditary hearing loss (Healing loss, HL) issued the expert specification of the variation interpretation guide (The 2018 HL-EP guideline) in evaluating the pathogenicity of OTOF gene variation in patients with auditory neuropathy. Methods:Thirty-eight auditory neuropathy patients with OTOF gene variant were selected as the study subjects (23 males and 15 females, aged 0.3-25.9 years). Using whole-genome sequencing, whole exome sequencing or target region sequencing (Panel) combined with Sanger sequencing, 38 cases were found to carry more than two OTOF mutation sites. A total of 59 candidate variants were independently interpreted based on the 2015 ACMG/AMP guideline and 2018 HL-EP guideline. Compared with the judgment results in 2015 ACMG/AMP guideline, the variants interpreted as lower pathogenic classifications in the 2018 HL-EP guideline were defined as downgraded variants, and the variants regarded as higher pathogenic classifications were defined as upgraded variants. Statistical analysis was conducted using SPSS 20.0. Results:The concordance rate of variant classification between the guidelines was 72.9%(43/59). The 13.6%(8/59) of variants were upgraded and 13.6% (8/59) of variants downgraded in the classifications of the 2018 HL-EP guideline. A couple of rules saw significant differences between the guidelines (PVS1, PM3, PP2, PP3 and PP5). The distribution of pathogenicity of splicing mutation was statistically different ( P=0.013). Conclusions:The 2018 HL-EP guideline is inconsistent with the 2015 ACMG/AMP guideline, when judging the pathogenicity of OTOF gene variants in patients with auditory neuropathy. Through the deletion and refinement of evidence and the breaking of solidification thinking, the 2018 HL-EP guideline makes the pathogenicity grading more traceable and improves the credibility.
