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Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus
Human Mutation ( IF 3.3 ) Pub Date : 2020-11-10 , DOI: 10.1002/humu.24136 Aboulfazl Rad 1 , Thore Schade-Mann 1 , Philipp Gamerdinger 1 , Grigoriy A Yanus 2, 3 , Björn Schulte 4 , Marcus Müller 1 , Evgeny N Imyanitov 2, 3, 5 , Saskia Biskup 4 , Hubert Löwenheim 1 , Anke Tropitzsch 1 , Barbara Vona 1
Human Mutation ( IF 3.3 ) Pub Date : 2020-11-10 , DOI: 10.1002/humu.24136 Aboulfazl Rad 1 , Thore Schade-Mann 1 , Philipp Gamerdinger 1 , Grigoriy A Yanus 2, 3 , Björn Schulte 4 , Marcus Müller 1 , Evgeny N Imyanitov 2, 3, 5 , Saskia Biskup 4 , Hubert Löwenheim 1 , Anke Tropitzsch 1 , Barbara Vona 1
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Alpha‐chain collagen molecules encoded by genes that include COL11A1 are essential for skeletal, ocular, and auditory function. COL11A1 variants have been reported in syndromes involving these organ systems. However, a description of the complete clinical spectrum is lacking, as evidenced by a recent association of autosomal dominant nonsyndromic hearing loss due to a splice‐altering variant in COL11A1, mapping the DFNA37 locus. Here, we describe two German families presenting prelingual autosomal dominant nonsyndromic hearing loss with novel COL11A1 heterozygous splice‐altering variants (c.652‐1G>C and c.4338+2T>C) that were molecularly characterized. Interestingly, the c.652‐1G>C variant affects the same intron 4 canonical splice site originally reported in the DFNA37 family (c.652‐2A>C) but elicits a different splicing outcome. Furthermore, the c.4338+2T>C variant originated de novo. We provide clinical and molecular genetic evidence to unambiguously confirm that COL11A1 splice‐altering variants cause DFNA37 hearing loss and affirm that COL11A1 be included in the genetic testing of patients with nonsyndromic deafness.
中文翻译：
异常 COL11A1 剪接导致 DFNA37 基因座中的语前常染色体显性非综合征性听力损失
由包括COL11A1在内的基因编码的 α 链胶原分子对骨骼、眼睛和听觉功能至关重要。COL11A1变异体已在涉及这些器官系统的综合征中报道。然而，缺乏对完整临床谱的描述，最近发现由于COL11A1中的一个剪接改变变体导致的常染色体显性遗传非综合征性听力损失关联，映射了 DFNA37 基因座。在这里，我们描述了两个具有新型COL11A1的语言前常染色体显性遗传非综合征性听力损失的德国家庭具有分子特征的杂合剪接改变变体（c.652-1G>C 和 c.4338+2T>C）。有趣的是，c.652-1G>C 变体影响最初在 DFNA37 家族中报道的相同的内含子 4 规范剪接位点（c.652-2A>C），但会引发不同的剪接结果。此外，c.4338+2T>C 变体从头开始。我们提供临床和分子遗传学证据以明确证实COL11A1剪接改变变体导致 DFNA37 听力损失，并确认COL11A1被包括在非综合征性耳聋患者的基因检测中。
更新日期：2020-12-26
中文翻译：
异常 COL11A1 剪接导致 DFNA37 基因座中的语前常染色体显性非综合征性听力损失
由包括COL11A1在内的基因编码的 α 链胶原分子对骨骼、眼睛和听觉功能至关重要。COL11A1变异体已在涉及这些器官系统的综合征中报道。然而，缺乏对完整临床谱的描述，最近发现由于COL11A1中的一个剪接改变变体导致的常染色体显性遗传非综合征性听力损失关联，映射了 DFNA37 基因座。在这里，我们描述了两个具有新型COL11A1的语言前常染色体显性遗传非综合征性听力损失的德国家庭具有分子特征的杂合剪接改变变体（c.652-1G>C 和 c.4338+2T>C）。有趣的是，c.652-1G>C 变体影响最初在 DFNA37 家族中报道的相同的内含子 4 规范剪接位点（c.652-2A>C），但会引发不同的剪接结果。此外，c.4338+2T>C 变体从头开始。我们提供临床和分子遗传学证据以明确证实COL11A1剪接改变变体导致 DFNA37 听力损失，并确认COL11A1被包括在非综合征性耳聋患者的基因检测中。
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