Objective To investigate the genotype and phenotype in patients with leber congenital amaurosis (LCA), and offer accurate genetic counseling and prenatal diagnosis for those families. Methods Three LCA patients and their parents were recruited for this study and received detailed collection of medical history and family history from March to August 2016. The three patients received fundus fluorescein angiography examination and their parents received slit-lamp microscope and indirect ophthalmoscopy examinations. DNA was extracted from the patients and their family members. Whole-exome sequencing method was used for genetic diagnosis and typing of the three LCA patients and their parents. Results The three patients with different clinical features had a definite clinical diagnosis of LCA. Patient 1 showed pale disc, attenuated vessels aroud the optic disc and the salt-and-pepper appearance of the retina, had the homozygous c.744.745insT (p.249, L>Ffs4) mutation inSPATA7. Patient 2 showed optic disc pallor and attenuated retinal vessels, had the heterozygous c.535G>A, p.A179T mutation inWFS1. Patient 3 showed pale disc, atrophic macular and retinal and choroidal degeneration, had the heterozygous mutation in CRB1, RPGRIP1, SPATA7. Conclusion LCA has characteristics of genetic heterogeneity and clinical and phenotypic diversity.
ObjectiveTo identify and observe the pathogenic gene variants and clinical phenotypes of two Han Chinese families with X-linked retinitis pigmentosa (XLRP). MethodsA family-based investigation study. Two unrelated Han Chinese XLRP families, whose probands were diagnosed via genetic testing after clinical visits at Xiamen Eye Center in 2019 and 2025 respectively, were enrolled in this study, including 7 and 51 family members correspondingly. Detailed family history, marital-reproductive history and systemic disease history were collected. Ophthalmic examinations including best-corrected visual acuity (BCVA), fundus color photography, optical coherence tomography (OCT) and full-field electroretinogram (ERG) were performed. Peripheral venous blood samples were collected from participants for whole-genomic DNA extraction. Whole-exome sequencing was applied to screen pathogenic variants, and Sanger sequencing was used for familial validation of candidate variant sites. Pathogenicity of the variants was assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines, together with online bioinformatic tools including SIFT, Mutation Taster, CADD and RDDC. ResultsThe proband of family 1 (F1-Ⅱ3), a 33-year-old male, presented with night blindness since childhood. His BCVA was 0.04 in the right eye and 0.05 in the left eye. Multifunctional bone-spicule-like pigment depositions were observed in the temporal retina of both eyes. OCT revealed focal thickening of the retinal pigment epithelium and loss of ellipsoid zone reflectivity. No stable rod- or cone-derived responses were detected on full-field ERG. This family was affected for three consecutive generations, showing X-linked inheritance characteristics. The proband carried a semi-synonymous missense variant of the RP2 gene, c.353G>C (p.Arg118Pro, M1). The proband’s mother and eldest daughter carried a heterozygous variant of M1, while the father and second son were wild-type. The proband of family 2 (F2-Ⅳ4) was a 6-year-old female. She had poor vision since childhood. At 8 months of age, she was found to have high astigmatism in both eyes during a physical examination. From the age of 4, she received amblyopia training but her vision did not show significant improvement. The full-field ERG showed decreased a-wave amplitude during dark adaptation and normal latency, decreased b-wave amplitude with delayed latency, and decreased a and b-wave amplitudes during bright adaptation with normal latency in all. This family had multiple members with poor vision since childhood and relying on refractive correction, with the disease affecting three consecutive generations. Male patients only passed the pathogenic gene to their daughters, which conforms to the X-linked dominant inheritance pattern. The proband carried a heterozygous small deletion variant of the RPGR gene, c.2405_2406del (p.Glu802Glyfs*32, M2). The father carried a semi-heterozygous small deletion variant of M2, while the mother and younger brother were wild-type. This variant co-segregated in all affected males, and some women carrying this variant also exhibited the corresponding clinical phenotype. Bioinformatics analysis showed that the M1 and M2 variants were predicted to be harmful by CADD, RDDC, SIFT, and Mutation Taster; M1 was not included in the gnomAD database and was a new rare variant; M2 was a known variant in the ClinVar database. According to the ACMG guidelines, both M1 and M2 were rated as likely pathogenic variants.ConclusionsThe hemizygous missense variant M1 in RP2 and the hemizygous small deletion variant M2 in RPGR are likely pathogenic variants for family 1 and family 2, respectively. M1 represents a previously unreported novel variant.