Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus

Authors

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

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.
Department of Tumor Growth Biology, N. N. Petrov Institute of Oncology, Saint Petersburg, Russia.
CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany.
Department of Oncology, I. I. Mechnikov North-Western Medical University, Saint Petersburg, Russia.

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.

Keywords: COL11A1; DFNA37; autosomal dominant hearing loss; nonsyndromic hearing loss; splice-site altering variant.