Novel ATF6 luminal domain variant in Achromatopsia

Background Gene variants in the unfolded protein response regulator activating transcription factor 6 (ATF6) are linked to achromatopsia (ACHM), an autosomal recessive cone dystrophy that impairs color vision and visual acuity. While most known variants appear in the transcriptional activator cytosolic region, the function and clinical impact of stress-sensing luminal domain variants remain poorly understood.Methods A patient with ACHM from a family carrying a new luminal domain ATF6 variant was clinically evaluated. Genetic testing was performed and compared to reference ATF6 sequence NM_007348.4. Deleterious ATF6 variants were analyzed using gnomAD allele frequencies, Combined Annotation Dependent Depletion (CADD) scores, multispecies sequence alignment, and spliceAI delta scores.Results An 18-year-old male from Taiwan presented with a homozygous missense exonic splice-region variant (c.1604G>A, p.Ser535Asn), bilateral foveal hypoplasia, disrupted inner outer photoreceptor segment layers, impaired color vision, and absent photopic but preserved scotopic responses. All known deleterious ATF6 variants had gnomAD frequencies below 0.0000627, and most were predicted to be deleterious by CADD.Conclusions Clinical and genetic characterization of this new luminal ATF6 variant in an affected individual highlights the critical importance of the ATF6 stress-sensing luminal domain for normal visual function.