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USH is autosomal recessively inherited and characterized by rod\u2010cone dystrophy or retinitis pigmentosa (RP), often accompanied by sensorineural hearing loss. Variants in &gt;15 genes have been identified as causative for clinically and genetically distinct subtypes. Among the ultra\u2010rare and recently discovered genes is <jats:italic>ARSG<\/jats:italic>, coding for the lysosomal sulfatase Arylsulfatase G. This subtype was assigned as \u201cUSH IV\u201d with a late onset of RP and usually late\u2010onset progressive SNHL without vestibular involvement. Here, we describe nine new subjects and the clinical description of four cases with the USH IV phenotype bearing seven novel and two known pathogenic variants. Functional experiments indicated the complete loss of sulfatase enzymatic activity upon ectopic expression of mutated <jats:italic>ARSG<\/jats:italic> cDNA. Interestingly, we identified a homozygous missense variant, p.(Arg99His), previously described in dogs with neuronal ceroid lipofuscinosis. Our study expands the genetic landscape of <jats:italic>ARSG<\/jats:italic>\u2010USH IV and the number of known subjects by more than 30%. These findings highlight that USH IV likely has been underdiagnosed and emphasize the need to test molecularly unresolved subjects with deafblindness syndrome. Finally, testing of <jats:italic>ARSG<\/jats:italic> should be considered for the genetic work\u2010up of apparent isolated inherited retinal diseases.<\/jats:p>","DOI":"10.1111\/cge.14614","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T04:50:57Z","timestamp":1724907057000},"page":"44-55","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Expanding the genetic landscape of Usher syndrome type <scp>IV<\/scp> caused by pathogenic <i>ARSG<\/i> variants"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0402-9006","authenticated-orcid":false,"given":"Miriam","family":"Bauwens","sequence":"first","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital &amp; Department of Biomolecular Medicine Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"De Man","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University Hospital Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0698-5309","authenticated-orcid":false,"given":"Isabelle","family":"Audo","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS Institut de la Vision  Paris France"},{"name":"Centre Hospitalier National d'Ophtalmologie des Quinze\u2010Vingts Centre de R\u00e9f\u00e9rence Maladies Rares REFERET and INSERM\u2010DGOS CIC 1423  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Balikova","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University Hospital Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wadih M.","family":"Zein","sequence":"additional","affiliation":[{"name":"Ophthalmic Genetics and Visual Function Branch NEI, NIH  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Belgium"},{"name":"Department of Neurosciences, Research Group Experimental Oto\u2010Rhino\u2010Laryngology (ExpORL), KU Leuven University of Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Jacob","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University Hospital Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingele","family":"Casteels","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University Hospital Leuven  Leuven Belgium"},{"name":"Biomedical Sciences Group, Department of Neurosciences Research Group Ophthalmology  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"D\u00e9sir","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Institut de Pathologie et de G\u00e9n\u00e9tique Gosselies  Charleroi Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Depasse","sequence":"additional","affiliation":[{"name":"Department of Pediatric Ophthalmology Queen Fabiola Children's University Hospital (HUDERF)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn","family":"Van de Sompele","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital &amp; Department of Biomolecular Medicine Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattias","family":"Van Heetvelde","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital &amp; Department of Biomolecular Medicine Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke","family":"De Bruyne","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University 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e Universit\u00e1rio de Coimbra (CHUC)  Coimbra Portugal"},{"name":"University Clinic of Ophthalmology, Faculty of Medicine University of Coimbra (FMUC)  Coimbra Portugal"},{"name":"Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine University of Coimbra (FMUC)  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Zeitz","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS Institut de la Vision  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elfride","family":"De Baere","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital &amp; Department of Biomolecular Medicine Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Damme","sequence":"additional","affiliation":[{"name":"Christian\u2010Albrechts\u2010University Kiel Institute of Biochemistry 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