Enrichment of LOVD-USHbases with 152 USH2A Genotypes Defines an Extensive Mutational Spectrum and Highlights Missense Hotspots

Alterations of USH2 encoding are responsible for more than '7 ages Usher s syndrome type (USH2), a recessive disorder he loss and retinal degedes usherM isoform 5.202-amino-ai. d p with an exceptional a e extracellul nsisting notably of a Lan-limn Nteuninal domain and numer, inin EGFdike (LE) and Fibronectin type 111 (EN3) re ations o are scattere t ro t e gene ari private. Annotatitig these variants is theret uajor p o correctly assign pathogenicity. We have x sively genotyp d a novel cohort of 152 Usher patients arid ideritified 58 different mutations, of which 93 are nen ly d bed. Pool, g this new data with the existing pathogenic vart alread ed bases reveals several previously unappr ed of the mutational spectrum. 'We show that parts p a ikeh Aerate single amino acid variations-, hereas o hers ti ute pathogenic misserise hotspots. We have nd, rept-E and FN3 domains, a nonequal distributio the missense mutat that highlights some crucial positions iri usherin with pos sequerices for the assessment of the pathogenicity nu u ense variants identified in USH2A.