A novel copy number variant in the murine Cdh23 gene gives rise to profound deafness and vestibular dysfunction

Abstract Hearing loss is the most common congenital sensory deficit worldwide and exhibits high genetic heterogeneity, making molecular diagnoses elusive for most individuals. Detecting novel mutations that contribute to hearing loss is crucial to providing accurate personalized diagnoses, tailored...

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Published in:	Human molecular genetics Vol. 33; no. 19; pp. 1648 - 1659
Main Authors:	Boehler, Nicholas A, Seheult, Shane D I, Wahid, Muhammad, Hase, Kazuma, D’Amico, Sierra F, Saini, Shakshi, Mascarenhas, Brittany, Bergman, Matthew E, Phillips, Michael A, Faure, Paul A, Cheng, Hai-Ying Mary
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 19-09-2024
Subjects:	Animals Cadherin Related Proteins Cadherins - genetics Deafness - genetics Disease Models, Animal DNA Copy Number Variations - genetics Hexokinase - genetics Humans Mice Mice, Inbred C57BL Mutation Original Phenotype Vestibular Diseases - genetics Whole Genome Sequencing auditory brainstem response hearing loss copy number variation spontaneous mouse mutant cadherin 23
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Summary:	Abstract Hearing loss is the most common congenital sensory deficit worldwide and exhibits high genetic heterogeneity, making molecular diagnoses elusive for most individuals. Detecting novel mutations that contribute to hearing loss is crucial to providing accurate personalized diagnoses, tailored interventions, and improving prognosis. Copy number variants (CNVs) are structural mutations that are understudied, potential contributors to hearing loss. Here, we present the Abnormal Wobbly Gait (AWG) mouse, the first documented mutant exhibiting waltzer-like locomotor dysfunction, hyperactivity, circling behaviour, and profound deafness caused by a spontaneous CNV deletion in cadherin 23 (Cdh23). We were unable to identify the causative mutation through a conventional whole-genome sequencing (WGS) and variant detection pipeline, but instead found a linked variant in hexokinase 1 (Hk1) that was insufficient to recapitulate the AWG phenotype when introduced into C57BL/6J mice using CRISPR-Cas9. Investigating nearby deafness-associated genes revealed a pronounced downregulation of Cdh23 mRNA and a complete absence of full-length CDH23 protein, which is critical for the development and maintenance of inner ear hair cells, in whole head extracts from AWG neonates. Manual inspection of WGS read depth plots of the Cdh23 locus revealed a putative 10.4 kb genomic deletion of exons 11 and 12 that was validated by PCR and Sanger sequencing. This study underscores the imperative to refine variant detection strategies to permit identification of pathogenic CNVs easily missed by conventional variant calling to enhance diagnostic precision and ultimately improve clinical outcomes for individuals with genetically heterogenous disorders such as hearing loss.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0964-6906 1460-2083 1460-2083
DOI:	10.1093/hmg/ddae095