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.

To analyze the pathogenicity and clinical features of patients in a consanguineous cone-rod dystrophy (CRD) family due to heterozygous variants in the GUCY2D gene.

Whole exome sequencing was used to screen for pathogenic genes and candidate pathogenic variants were obtained by bioinformatics analysis. Sanger sequencing was used for validation and familial co-segregation analysis to determine pathogenic variants. Pymol software was applied to produce a 3D structure image of the protein to analyze the structural and functional alterations of the protein. The pathogenicity of genetic variants was evaluated according to ACMG guidelines.

The chief clinical symptoms of this proband included obvious visual impairment, protanopia and deuteranopia, peripheral punctate pigment, arteriolar attenuation, structural and functional abnormalities revealed by optical coherence tomography (OCT) and electroretinography (ERG) including thinning of the outer retinal layer, a discontinuous external limiting membrane (ELM) and ellipsoid zone (EZ), granular hyperreflective projections between the retinal pigment epithelium and the interdigitation zone, severe attenuation of photopic responses with mild reduced scotopic responses. Whole-exome sequencing revealed that the proband carried a heterozygous variant of the GUCY2D gene: c.2512C>T: p.Arg838Cys. Three-dimensional molecular structure analysis of the protein revealed that amino acid 838 was mutated from polar positively charged arginine to polar uncharged cysteine, and the spatial structure of the protein changed greatly. Sanger sequencing co-segregation analysis confirmed that such a variant was detected in neither the phenotypically normal parents nor the daughter of the proband, which was presumed to be a de novo one. The variant was determined to be pathogenic according to ACMG guidelines. The heterozygous variant at the same site was detected in the abnormal proband’s son with moderate attenuation of photopic electroretinographic responses and normal scotopic electroretinographic responses, supporting autosomal dominant inheritance.

The de novo variant causing atypical autosomal dominant CRD is identified in a Chinese consanguineous family and this variant passes through this family in an autosomal dominant mode of inheritance, revealing the complex diversity and unpredictability of the inheritance mode for common single-gene genetic disease.

To investigate the genetic and clinical characteristics of patients with a large heterozygous copy number deletion on 7q31.31-7q31.32.

A family with familial exudative vitreoretinopathy (FEVR) phenotype was included in the study. Whole-exome sequencing (WES) was initially used to locate copy number variations (CNVs) on 7q31.31-31.32, but failed to detect the precise breakpoint. The long-read sequencing, Oxford Nanopore sequencing Technology (ONT) was used to get the accurate breakpoint which is verified by quantitative real-time polymerase chain reaction (QPCR) and Sanger Sequencing.

The proband, along with her father and younger brother, were found to have a heterozygous 4.5 Mb CNV deletion located on 7q31.31-31.32, which included the FEVR-related gene TSPAN12. The specific deletion was confirmed as del(7)(q31.31q31.32)chr7:g.119451239_123956818del. The proband exhibited a phase 2A FEVR phenotype, characterized by a falciform retinal fold, macular dragging, and peripheral neovascularization with leaking of fluorescence. These symptoms led to a significant decrease in visual acuity in both eyes. On the other hand, the affected father and younger brother showed a milder phenotype.

The heterozygous CNV deletion located on 7q31.31-7q31.32 is associated with the FEVR phenotype. The use of long-read sequencing techniques is essential for accurate molecular diagnosis of genetic disorders.