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Four previously published families have replicated autosomal recessive non-syndromic hearing loss (DFNB106), yet the mutational and clinical spectrum remains poorly described. This study expands the mutational and clinical spectrum of\n                    <jats:italic>EPS8L2<\/jats:italic>\n                    -associated hearing impairment by identifying five additional individuals in four families, more than doubling the number of reported cases to date, while going deeper into clinical aspects. These include two frameshift variants c.818_827dup, p.(Ala279Glyfs*36) and c.1430dup, p.(Val478Serfs*25), the first nonsense variant c.1878C\u2009&gt;\u2009A, p.(Tyr626Ter), and the first missense variant with a spliceogenic effect c.767C\u2009&gt;\u2009G, p.(Thr256Arg). Functional analysis confirmed that the c.767C\u2009&gt;\u2009G variant causes exon 9 skipping, leading to a frameshift r.701_768del, p.(Gly234Alafs*55). A shared 4.17\u00a0Mb homozygous region among two unrelated Iranian families with this variant suggested a founder effect. These individuals uniquely showed U-shaped audiograms as a new association of more severe middle frequency hearing loss. Clinically, affected individuals presented moderate to moderately severe hearing loss that was mostly progressive, with an onset starting between the prelingual stage, extending postlingually. A younger sibling of the first European proband diagnosed with DFNB106 passed newborn hearing screening but was identified with compound heterozygous variants, underscoring the importance of early genetic testing. The progressive nature of\n                    <jats:italic>EPS8L2<\/jats:italic>\n                    -related hearing loss is unusual for recessive non-syndromic forms and highlights the need for early monitoring and intervention. This work emphasizes the need for early molecular diagnosis and long-term clinical follow-up, while describing the natural history of\n                    <jats:italic>EPS8L2<\/jats:italic>\n                    that will be important for future therapeutic development.\n                  <\/jats:p>","DOI":"10.1007\/s12035-025-05615-9","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T23:50:38Z","timestamp":1768002638000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expansion of Molecular and Clinical Aspects of EPS8L2 (DFNB106)-Associated Hearing Loss Emphasizes a Potential Therapeutic Window"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3055-3613","authenticated-orcid":false,"given":"Daniel","family":"Owrang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8627-8828","authenticated-orcid":false,"given":"Aboulfazl","family":"Rad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masoome","family":"Alerasool","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne M.","family":"Kolb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7559-6529","authenticated-orcid":false,"given":"Sheng-Jia","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0037-9079","authenticated-orcid":false,"given":"Julia","family":"Doll","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neda","family":"Alidadiani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0124-3026","authenticated-orcid":false,"given":"Shahrooz","family":"Ghaderi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela A. 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