ObjectiveTo observe and analyze the pathogenic genes and clinical phenotype characteristics of retinitis pigmentosa sinepigmento(RPSP). MethodsA retrospective clinical study. Two patients (proband) and five family members from two RPSP families admitted to Xiamen Eye Center of Xiamen University in December 2022 and Shenzhen Eye Hospital in July 2023 were included in the study. Two families have no blood relationship and were both Han Chinese. Detailed ocular and systemic medical history and specialized examinations were performed for all members, including color fundus photography, fundus autofluorescence (FAF), and full field electroretinogram (ff-ERG) examination. The peripheral venous blood of all members was collected, and genomic DNA was extracted. Pathogenic genes and their loci were screened using whole exome high-throughput sequencing technology. Sanger sequencing was used to verify the pathogenic genes in the two pedigrees. The pathogenicity of candidate variants was evaluated according to the American Society for American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants. ResultsThe two probands were male, aged 9 and 7 years, respectively. The main complaint was poor binocular vision for 6 and 3 years and poor treatment effect of amblyopia. The proband (Ⅱ2) in family 1 had a pale red color on the optic disc, with leopard-like changes in the posterior pole and thinner retinal arteries. FAF showed mottled fluorescence attenuation outside the macular vascular arch. There was no significant waveform in both bright and dark visual responses of ff-ERG. He also had 6-toed deformity of both feet, renal cysts, and a slightly overweight body. The clinical diagnosis was non-pigmentary retinitis pigmentosa. The proband of family 2 (Ⅱ1) had poor binocular vision in a dark environment and had atrophy lesions on the nasal side of the optic disc and leopard print like changes in the fundus. FAF showed uneven enhancement in the fovea. ff-ERG showed severe abnormalities in dark and light response, with significant decrease and delay in b-wave amplitude and latency. He had no other systemic abnormalities. The clinical diagnosis was binocular RPSP. There were no abnormal ocular and systemic manifestations in the two family members. Gene sequencing revealed a homozygous mutation (c.534+1G>T) of BBS2 gene, which was inherited from the mother and father respectively. Based on clinical manifestations and genetic testing results, the final diagnosis was Bardet Biedl syndrome. The genetic sequencing results confirmed a novel compound heterozygous mutation (c.950T>G: p. Leu317Arg missense mutation and c.849+1G>C splicing mutation) of BBS7 gene. His father (Ⅰ1) and mother (Ⅰ2) carried M1 heterozygous variants. Combined with the clinical manifestations and genetic testing results, the final diagnosis was Bardet-Biedl syndrome (BBS). Family 2 proband (Ⅱ1) carried the BBS7 gene C.950T>G (p.Leu317Arg) (M2) missense variation and C.849 +1G>C (M3) splice site variation. His father (Ⅰ1) and mother (Ⅰ2) carried M3 shear site variation and M2 missense variation, respectively. The two families all fit the autosomal recessive inheritance pattern, and the genotype and clinical phenotype were coseparated. According to ACMG guidelines, M1, M2 and M3 were all identified as possible pathogenic variants. ConclusionsBBS2 gene M1 homozygous variation and BBS7 gene M2, M3 complex heterozygous variation are the possible pathogenic genes in family 1 and family 2, respectively. Two families are affected by BBS and RPSP, respectively.
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.