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

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

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.

© 2020 The Authors. Human Mutation published by Wiley Periodicals LLC.