Clinical and Genetic Spectrum of OPN1LW/OPN1MW-Associated Disorders in a Chinese Cohort: Contribution of Long-Read Sequencing

The highly homologous OPN1LW/OPN1MW gene cluster poses substantial challenges for molecular diagnosis. We retrospectively enrolled 12 male patients from 10 unrelated Chinese families with clinically suspected X-linked cone-opsin disorder, all of whom were confirmed to carry disease-associated variants or haplotypes in the OPN1LW/OPN1MW gene cluster. Clinical records, retinal imaging, electrophysiology, and available ocular biometry were analyzed together with short-read sequencing, Sanger validation, copy-number analysis, and Oxford Nanopore long-read sequencing for three cases with incomplete short-read resolution. Clinical subgroups included blue cone monochromacy (n = 5), X-linked cone dystrophy (n = 4), Bornholm eye disease (n = 2), and isolated color-vision deficiency (n = 1). Molecular results encompassed sequence variants, exon dosage alterations, a 51.8 kb deletion involving the locus control region, and exon 3 haplotypes. Long-read sequencing defined the deletion breakpoint in one case and the exon 3 haplotypes in two. In one boy with an X-linked cone dystrophy phenotype, the mean binocular axial length increased from 25.36 mm to 28.47 mm between 1.80 and 6.24 years of age. Our findings demonstrate the complementary utility of multimodal molecular assays and heterogeneous phenotypes of cone-opsin disorders, with sustained childhood axial elongation reported only as a single-case observation.