中国人集団における聴覚神経障害の高頻度変異と表現型進行

High Frequency of Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population.

• Hongyang Wang
• Dan Bing
• Jin Li
• Linyi Xie
• Fen Xiong
• Lan Lan
• Dayong Wang
• Jing Guan
• Qiuju Wang

抄録

変異に起因する聴覚神経障害（AN）の遺伝子型とフェノタイプの相関を解読し，これらの患者の表現型の進行を明らかにすることで，ANの潜在的な分子的な発症機序を探ることを目的とした．聴覚神経障害のバリエーションを有する36家族（50例）を募集し，Sanger塩基配列決定法または次世代塩基配列決定法により同定した．その結果、晩発型AN患者の18.6％が-陽性であることが判明しました。変異型を有するAN患者50人のうち，男性45人，女性5人であった．この遺伝子のホットスポット変異は p.Leu344Phe で、36.1％を占めていた。本研究では、7 つの新規変異を含む合計 19 の変異が報告された。以前に報告された30例の陽性者を対象に追跡調査が行われ、16例（53.3％）が本研究に含まれ、追跡期間は1年から23年、平均9.75±9.89年で記録された。短期フォローアップ期間（1～10年）では聴力閾値の上昇は見られなかったが、低周波聴力閾値と高周波聴力閾値はフォローアップ期間の延長に伴って有意な上昇を示した。音声弁別スコアは、病状の経過に沿って徐々に有意に進行し、純音閾値よりも不釣り合いに悪化する深刻な低下を示した。また、-related ANでは、X-linked recessive 遺伝パターンに加えて、X-linked dominant 遺伝パターンも認められ、女性に影響を及ぼすことが示唆された。結論として、晩発型AN症例では主な関連遺伝子はLeu344Pheであり、最も多い再発変異はp.Leu344Pheであることが確認されました。X-linked recessive 遺伝パターンを除き、X-linked dominant 遺伝パターンは-related AN のもう一つの確率であり、女性が罹患します。関連するANの表現型の特徴は、時間の経過とともに聴覚の非同期性が徐々に悪化していくことを示唆しています。

To decipher the genotype-phenotype correlation of auditory neuropathy (AN) caused by variations, as well as the phenotype progression of these patients, exploring the potential molecular pathogenic mechanism of AN. A total of 36 families of individuals with AN (50 cases) with variations were recruited and identified by Sanger sequencing or next-generation sequencing; the participants included 30 patients from 16 reported families and 20 new cases. We found that -positive cases accounted for 18.6% of late-onset AN cases. Of the 50 AN patients with variants, 45 were male and 5 were female. The hotspot variation of this gene was p.Leu344Phe, accounting for 36.1%. A total of 19 variants were reported in this study, including 7 novel ones. A follow-up study was performed on 30 previously reported positive subjects, 16 follow-up cases (53.3%) were included in this study, and follow-up periods were recorded from 1 to 23 years with average 9.75 ± 9.89 years. There was no hearing threshold increase during the short-term follow-up period (1-10 years), but the low-frequency and high-frequency hearing thresholds showed a significant increase with the prolongation of follow-up time. The speech discrimination score progressed gradually and significantly along with the course of the disease and showed a more serious decline, which was disproportionately worse than the pure tone threshold. In addition to the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is also observed in -related AN and affects females. In conclusion, we confirmed that is the primary related gene among late-onset AN cases, and the most common recurrent variant is p.Leu344Phe. Except for the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is another probability of -related AN, with females affected. Phenotypical features of -related AN suggested that auditory dyssynchrony progressively worsened over time.

Copyright © 2020 Hongyang Wang et al.