Early-Onset Retinopathy in Patients With Variants in SLC6A6 Leading to Impaired Taurine Transport.
IMPORTANCE: Inherited retinal dystrophies are a group of disorders that may lead to progressive vision loss. Improved knowledge of their molecular genetics is important for accurate diagnosis or development of targeted therapies. OBJECTIVE: To identify pathogenic variants in the SLC6A6 gene (encoding TauT, the main transporter for taurine) and assess their role in the molecular pathogenesis of hereditary early-onset retinal dystrophy (EORD) in affected individuals from diverse ethnic backgrounds. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, multicenter observational study conducted between June 2019 and March 2025, involving 7 affected and 10 unaffected individuals from 4 unrelated families recruited in Pakistan, Italy, the US, and France. EXPOSURE: Pathogenic variants in SLC6A6 in individuals with EORD. MAIN OUTCOMES AND MEASURES: Genetic, clinical, and functional outcomes of pathogenic variants in SLC6A6 in individuals with Leber congenital amaurosis (LCA) and EORD. All patients underwent standard clinical examinations, including visual acuity, full-field electroretinography, and multimodal retinal imaging, followed by measurement of fasting plasma taurine levels. In vitro and ex vivo taurine transport and membrane trafficking assays in human embryonic kidney (HEK)-293 cells, as well as patient-derived fibroblasts, were also performed. RESULTS: All 7 affected individuals exhibited LCA/EORD, with extraocular findings in some. Genetic analysis identified homozygous pathogenic SLC6A6 variants in all affected individuals, while unaffected relatives were heterozygous carriers. Families 1 and 2 carried missense variants p.(Thr249Ile) and p.(Ala294Thr), while families 3 and 4 carried truncating variants-a deletion of exon 11 and p.(Thr113Ter), respectively. Functional studies demonstrated that both missense variants are associated with complete loss of taurine transport in HEK-293 cells and patient-derived fibroblasts. Additionally, irrespective of the variants considered, plasma taurine levels in affected individuals were reduced compared with heterozygous carriers (difference between means, -31.7 µmol/L; 95% CI, -42.7 to -20.8; P < .001) and healthy control individuals (difference between means, -37.7 µmol/L; 95% CI -41.6 to -33.8; P < .001). CONCLUSIONS AND RELEVANCE: These findings confirm and expand the role of biallelic variants in SLC6A6 in association with LCA/EORD due to impaired taurine transport. These findings suggest that patients with a diagnosis of SLC6A6-related LCA/EORD may be candidates for investigational oral taurine supplementation.