DFNA68 is a rare subtype of autosomal dominant nonsyndromic hearing impairment caused by heterozygous alterations in the HOMER2 gene. To date, only 5 pathogenic or likely pathogenic coding variants, including two missense substitutions (c.188 C > T and c.587 G > C), a single base pair duplication (c.840dupC) and two short deletions (c.592_597delACCACA and c.832_836delCCTCA) have been described in 5 families. In this study, we report a novel HOMER2 variation, identified by massively parallel sequencing, in a Sicilian family suffering from progressive dominant hearing loss over 3 generations. This novel alteration is a nonstop substitution (c.1064 A > G) that converts the translational termination codon (TAG) of the gene into a tryptophan codon (TGG) and is predicted to extend the HOMER2 protein by 10 amino acids. RNA analyses from the proband suggested that HOMER2 transcripts carrying the nonstop variant escaped the non-stop decay pathway. Finally, in vivo studies using a zebrafish animal model and behavioral tests clearly established the deleterious impact of this novel HOMER2 alteration on hearing function. This study identifies the fourth causal variation responsible for DFNA68 and describes a simple in vivo approach to assess the pathogenicity of candidate HOMER2 variants.
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The data that support this study are available from the corresponding author upon reasonable request. The variants, individual and phenotype described in this paper is available to the LOVD GVShared, Individual ID number #00411547 to #00411552 (e.g., https://databases.lovd.nl/shared/individuals/00411547).
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We are grateful to the family members who contributed to this study. We thank Dr Yoan Arribat, University of Lausanne (Switzerland), for his help with Gateway cloning and Dr Benjamin Cogné, CHU of Nantes (France), for the GATK pipeline.
This work was partially funded by the association SOS Rétinite France and the French Agency of BioMedicine (AOR AMP 2017).
The authors declare no competing interests.
The institutional review board (IRB) of CHU de Montpellier approved the experimental protocol (2018_IRB-MTP_05-05 obtained on the 15th June 2018). The zebrafish study was conducted in accordance with the recommendations of INSERM, Montpellier University and the European Convention for the Protection of Animals used for Experimental and Scientific Purposes.
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Vaché, C., Cubedo, N., Mansard, L. et al. Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss. Eur J Hum Genet 31, 834–840 (2023). https://doi.org/10.1038/s41431-023-01374-0
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