Rad Aboulfazl, Schade-Mann Thore, Gamerdinger Philipp, Yanus Grigoriy A, Schulte Björn, Müller Marcus, Imyanitov Evgeny N, Biskup Saskia, Löwenheim Hubert, Tropitzsch Anke, Vona Barbara
Department of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, Germany.
Department of Medical Genetics, Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia.
Hum Mutat. 2021 Jan;42(1):25-30. doi: 10.1002/humu.24136. Epub 2020 Nov 11.
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.
由包括COL11A1在内的基因编码的α链胶原蛋白分子对骨骼、眼部和听觉功能至关重要。COL11A1变体已在涉及这些器官系统的综合征中被报道。然而，由于最近发现COL11A1中一个剪接改变变体与常染色体显性非综合征性听力损失相关，定位了DFNA37位点，因此缺乏对完整临床谱的描述。在此，我们描述了两个德国家庭，他们表现为语前常染色体显性非综合征性听力损失，带有新的COL11A1杂合剪接改变变体（c.652 - 1G>C和c.4338 + 2T>C），并对其进行了分子特征分析。有趣的是，c.652 - 1G>C变体影响的是最初在DFNA37家系中报道的同一内含子4的典型剪接位点（c.652 - 2A>C），但引发了不同的剪接结果。此外，c.4338 + 2T>C变体是新生的。我们提供临床和分子遗传学证据，明确证实COL11A1剪接改变变体导致DFNA37听力损失，并确认COL11A1应纳入非综合征性耳聋患者的基因检测中。
