Genotype-phenotype correlations in Chinese patients with congenital stationary night blindness and early-onset high myopia: evidence from electrophysiology and whole-exome sequencing

To identify pathogenic variants in families with congenital stationary night blindness (CSNB) accompanied by early-onset high myopia (eoHM) using whole-exome sequencing (WES), and to evaluate the clinical value of electrophysiological and genetic testing for the differential diagnosis of CSNB, which is frequently misdiagnosed as amblyopia.

The study cohort comprised families clinically diagnosed with eoHM. Probands and available family members underwent comprehensive ophthalmic examinations. Pathogenic variants were identified via WES, in silico analysis, co-segregation analysis, Sanger sequencing and classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Genotype-phenotype correlations were analyzed within the context of CSNB, supplemented by a review of relevant literature utilizing databases including HGMD, PubMed, CNKI, and Wanfang.

Among 42 families with eoHM, five were identified with CSNB. The probands aged 2–5y, with spherical equivalents (SE) ranging from −6.00 to −11.00 D and best-corrected visual acuity (BCVA) between 0.15 and 0.6. No organic ocular abnormalities were observed. Initially diagnosed as high myopia and refractive amblyopia, they received optical correction and amblyopia therapy. Electroretinogram (ERG) revealed diminished rod responses and a negative waveform under dark-adapted 3.0 ERG conditions. Seven pathogenic variants were identified in CACNA1F, NYX, and TRPM1, including two novel variants. All five probands were ultimately diagnosed with CSNB-associated eoHM. In Family 1, the proband carrying a CACNA1F variant (c.1873C>T; p.Arg625Ter) exhibited slow myopic progression without fundus changes over 9y of follow-up. A literature review highlighted significant genetic and clinical heterogeneity in CSNB-related eoHM.

This study reveals marked genetic and clinical heterogeneity in CSNB-related eoHM. TRPM1 and NYX variants (complete CSNB) cause earlier and more severe myopia than CACNA1F variants (incomplete CSNB). Characteristic ERG patterns differentiate subtypes. Reduced BCVA in eoHM may indicate inherited retinal disorders, not just refractive errors. Children with eoHM and reduced BCVA need systematic electrophysiological and genetic evaluations to prevent misdiagnosis and enable personalized care.