DFNA37 (autosomal dominant non-syndromic hearing loss 37) is caused by COL11A1 variants – confirmatory evidence by a novel splicing variant

Hearing loss is an increasing burden in an aging society. Over 50 % of cases have a genetic background that are inherited in as autosomal dominant (DFNA), recessive (DFNB), X-linked (DFNX) and mitochondrial. Roughly 20 % of hearing impaired patients suffer from autosomal dominant non-syndromic hearing loss, making it the second most common cause. Most proteins are not specific to the inner ear. Mutations in genes coding for these proteins can cause syndromic hearing loss.

Autosomal dominantly inherited Marshall syndrome and Stickler syndrome type II, and autosomal recessive fibrochondrogenesis are associated with the gene COL11A1 (collagen type XI alpha 1 chain). Besides phenotypic manifestations of skeletal dysplasia, dysmorphic features, and cleft palate of variable shape, these disorders can include hearing loss. DFNA37 is an autosomal dominant non-syndromic hearing loss locus that recently has been associated with a novel splice-site alternating variant in the COL11A1 gene.

We identified a four generation family with non-syndromic hearing loss. The index patient presented with symmetric moderate sensorineural hearing loss without any further syndromic features. Using a custom-designed high-throughput sequencing panel (160 hearing loss-associated genes) we identified a variation in the COL11A1 gene. The in-silico analysis of the variant (c.4338+2T>C, p.?, NM_080629.2) is predicted to cause a splice-variant that abolishes the 5’ splice site in exon 58 (out of 68). This affects a highly conserved nucleotide of the alpha chain region. Abnormal splicing was confirmed by functional testing in an in-vitro splice assay.

The here reported second variant contributes to the body of evidence that COL11A1 can be causative for autosomal dominant non-syndromic hearing loss.

Poster-PDF A-1889.PDF

Publication History

Article published online:
10 June 2020