Background/Objectives: Knobloch syndrome 1 (KS) is an autosomal recessive inherited ocular syndrome characterized by a combination of high myopia, vitreoretinal degeneration, and occipital encephalocele. KS is caused by biallelic pathogenic variants in the COL18A1 gene. Diagnosing KS can be challenging due to its clinical heterogeneity and the rarity of the syndrome. Methods: We conducted comprehensive clinical and instrumental ophthalmological examinations, whole-exome sequencing, Sanger sequencing, and segregation analysis to evaluate affected families. Results: Two patients presenting with high myopia, low visual acuity, chorioretinal atrophy, and occipital skin/skull defects were diagnosed with Knobloch syndrome 1 (KS). In Case 1, a 14-year-old boy, the COL18A1 variants identified were c.2673dup and c.3523_3524del in a compound heterozygous state. Case 2 involved a 3-year-old girl, the c.1637_1638dup and c.3523_3524del variants were identified in a compound heterozygous state. In Case 3, a retrospectively observed boy of 3 y.o. with KS, the variants c.929-2A>G and c.3523_3524del were defined earlier. Conclusions: We confirmed KS molecularly in two novel families. Additionally, in Case 3 of a retrospectively analyzed third family and in both novel cases, one of the biallelic causative variants was the same known 2bp deletion in exon 40 of the collagen XVIII gene. Cases 1 and 3 were characterized by connective tissue dysplasia features and a pathognomonic Knobloch triad. No neurological manifestations and no trends in the genotype–phenotype relationship were found. The heterogeneity of phenotype in the case series is likely to be the result of further factors and/or genetic background.

Pathogenic variants in the USH2A gene are the primary cause of both non-syndromic autosomal recessive inherited retinitis pigmentosa (RP) and the syndromic form, characterized by retinal degeneration and sensorineural hearing loss. This study presents a comparative assessment of the genetic variant spectrum in the USH2A gene among Russian patients in two clinical groups. A retrospective analysis was conducted on massive parallel panel sequencing data from 2415 blood samples of unrelated patients suspected of having hereditary retinal diseases. The copy number of USH2A exons was determined using the quantitative MLPA method with the MRC-Holland SALSA MLPA kit. Biallelic pathogenic and likely pathogenic variants in the USH2A gene were identified in 69 patients (8.7%). In the group of patients with isolated hereditary RP (55 patients), the most frequent pathogenic variants were p.(Glu4445_Ser4449delinsAspLeu) (20.9%), p.(Trp3955*) (15.5%), and p.(Cys934Trp) (5.5%). In patients with the syndromic form (14 patients), the most frequent variants were p.(Trp3955*) (35.7%) and c.8682-9A>G (17.9%). It was found that patients with isolated vision impairment rarely had two “null” variants (17.8%), whereas this was common among patients with both hearing and vision impairment (71.4%) (p ≤ 0.05), explaining the severity of the disease and the earlier onset of clinical symptoms in the syndromic form of RP. Ten previously undescribed loss-of-function variants were identified. The estimated prevalence of USH2A-associated retinal dystrophy in Russia was 1.9 per 100,000 individuals. The obtained data on the differences in the spectra of genetic variants in the USH2A gene in the two studied groups highlight the importance of establishing genotype–phenotype correlations and predicting disease severity, aiming at potential early cochlear implantation and selection of target therapy.

Purpose. This study investigated the prevalence and morphofunctional characteristics of the retina in the diagnosis of various types of Leber congenital amaurosis (LCA) among patients from Moscow and the Moscow region, based on the data from the Consultative and Diagnostic Center of the Morozov Children’s City Clinical Hospital. Material and methods. In order to analyze the polymorphism and prevalence of LCA, the study examined a total of 226 patients suspected of having hereditary retinal dystrophies, genetic diagnosis of Leber amaurosis was confirmed in 24 patients. All 24 patients underwent electrophysiological tests, including visual evoked potentials (VEP) from the sensory retina to the visual centers, and electroretinography (ERG) of the posterior pole of the retina. In children over 5 years old, additional methods were used: optical coherence tomography (OCT), fundus photography, and fundus autofluorescence (FAF) using a fundus camera. Results. According to the molecular genetic analysis, the most frequent type was LCA type 10 (37%), followed by LCA type 2 (16%). The most common clinical manifestations among patients were nystagmus, impaired night vision, waxy optic disc pallor, narrowed arteries, and changes on the ERG. OCT revealed changes in the outer retinal layers in all patients. ERG showed abnormalities in 100% of the patients, with the maximal ERG either not being recorded or significantly reduced. During VEP, most patients exhibited configuration disturbances, increased latency, and a sharp decrease in the amplitude of the P100 component. Conclusion. The analysis of patients with genetically confirmed Leber amaurosis revealed that LCA type 10 caused by mutations in the CEP290 gene was the most common (37%), followed by LCA type 2 (16%) caused by mutations in the RPE65 gene.

The study purpose was to assess the diagnostic value of whole-genome sequencing (WGS) in identifying candidate genetic variants in patients with inherited retinal diseases (IRDs). We investigated 107 unrelated Russian patients with retinal diseases who carried single pathogenic variants in any of nine common autosomal recessive IRD genes (ABCA4, USH2A, EYS, CRB1, RPE65, CNGB3, CNGA3, CEP290, and GUCY2D). WGS was performed for all patients; candidate splice variants were functionally validated using minigene assays. The total diagnostic yield was 40.2% (43/107). In 25.2% of cases (27/107), the diagnosis was established by identifying a second variant in one of the following candidate genes: EYS (n = 9), USH2A (n = 8), ABCA4 (n = 5), CNGB3 (n = 3), CRB1 and CEP290 (n = 1 each). In 15.0% of cases (16/107), the diagnosis was reclassified by variants in alternative IRD genes (autosomal dominant, X-linked, mitochondrial, or syndromic). The majority of second variants detected in AR cases were CNVs (55.5%, 15 patients), followed by non-coding variants (26.0%, seven), structural rearrangements (14.8%, four) and exonic point variant (3.7%, one). Two recurrent CNVs were observed: a gross deletion of exons 22–24 in USH2A (n = 4) and a deletion partially affecting exon 19 of EYS (n = 4). Structural variants were mostly represented by delINV rearrangements (n = 5). Minigene assays confirmed that three novel deep intronic variants (in CHM, EYS, and CEP290) and one non-canonical splice-acceptor variant in USH2A which disrupt splicing, causes pseudoexon inclusion with premature termination or in-frame exon skipping respectively. Thus, WGS improves the diagnostic yield in IRDs by detecting variants missed by targeted sequencing, supporting its clinical utility in ophthalmologic practice.

Background/Objectives: Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy caused by variants in genes encoding components of the BBSome complex. Interpretation of rare variants in the BBS7 gene remains challenging, particularly for variants of uncertain significance. This study aimed to provide clinical and molecular genetic characterization of two siblings with a BBS phenotype harboring compound heterozygous variants in BBS7, including a previously undescribed missense variant. Methods: Two siblings (aged 11 and 8 years) presenting with obesity, postaxial polydactyly, retinal dystrophy, and cystic renal dysplasia were clinically evaluated. Whole-exome sequencing was performed in the proband, followed by segregation analysis within the family. Variant classification was conducted according to ACMG/AMP guidelines, integrating allele frequency data, in silico predictions, segregation evidence, and structural modeling. Results: Two heterozygous variants in the BBS7 gene (NM_176824.3) were identified in trans: a previously reported pathogenic frameshift variant, c.1967_1968delinsC, p.(Leu656ProfsTer18), and a missense variant, c.454T>C, p.(Cys152Arg), which, to the best of our knowledge, has not been previously reported in patients with Bardet–Biedl syndrome. The variant was extremely rare in population databases. Structural analysis suggested steric and electrostatic disruptions, including loss of a disulfide bond. Based on ACMG/AMP criteria, the variant was classified as likely pathogenic. Conclusions: This case supports the likely pathogenic classification of the c.454T>C, p.(Cys152Arg) variant. The findings highlight the importance of integrating clinical, genetic, and structural data for the interpretation of rare variants in BBS-associated genes.