Biomedical subjects

Vasily Smirnov

Publications and source records attributed to Vasily Smirnov.

3 recordsLinked to original sources

PubMed2026

Clinical and Genetic Spectrum of ACO2-Linked Dominant Optic Atrophy.

IMPORTANCE: Aconitase 2 (ACO2) gene variants are one of the most frequent causes of dominant optic atrophy (DOA). However, the associated phenotypes and genotypes still lack proper characterization. OBJECTIVE: To characterize the clinical and genetic spectrum of ACO2-related DOA and evaluate genotype-phenotype correlations. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective case series to describe the ophthalmological examination of novel DOA cases with a heterozygous ACO2 variant. Data were collected from 13 reference centers in ophthalmology from France and Great Britain between January 2021 and September 2025. Included participants were those patients with OA and confirmed heterozygous or compound heterozygous ACO2 variants. EXPOSURES: DOA cases with a heterozygous ACO2 variant. MAIN OUTCOMES AND MEASURES: Positive molecular diagnosis for ACO2 variants by next-generation sequencing, clinical examination including age at diagnosis, sex, best-corrected visual acuity (BCVA), retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness, visual field mean deviation (MD), and fundus examination. RESULTS: Data for 55 patients (median [IQR] age at diagnosis for 45 patients, 24 [8-51] years; 33 male [67%]) from 37 families with ACO2 variants were compiled. Analyses were conducted on 49 patients who were strictly heterozygous or compound heterozygous with the c.220C>G benign variant. Clinical data disclosed a high variability of severity, from pauci-symptomatic up to legal blindness. Median BCVA was 0.46 logMAR (Snellen equivalent, 20/63; IQR 0.00-0.89; n = 45). Four patients exhibited retinal abnormalities: 3 displayed a foveopathy, and 1 had retinitis pigmentosa. There were 12 previously unreported variants (to the authors' knowledge), including the deletion of ACO2 exon 9. No correlation between BCVA and sex, age at diagnosis (Spearman ρ = -0.19; 95% CI, -0.45 to 0.07), or variant type (Kruskal-Wallis test P =.33) was found, but there was a correlation between BCVA and RNFL (Spearman ρ = -0.74; 95% CI, -0.85 to -0.54), GCL (Spearman ρ = -0.60; 95% CI, -0.79 to -0.30), and MD (Spearman ρ = -0.65; 95% CI, -0.89 to -0.31). RNFL correlated with GCL (Spearman ρ = 0.69; 95% CI, 0.42-0.87) and MD (Spearman ρ = 0.57; 95% CI, 0.14-0.85); age at diagnosis correlated with GCL (Spearman ρ = -0.37; 95% CI, -0.63 to -0.03). CONCLUSIONS AND RELEVANCE: Results of this case series reveal the high clinical heterogeneity among patients with ACO2-related DOA and demonstrated that some of these patients can also exhibit retinal abnormalities. In addition, there was a deletion of an entire ACO2 exon, emphasizing the potential importance of searching for large genomic rearrangements in patients without a molecular diagnosis. These findings support further studies to explain clinical variability, as no genotype-phenotype correlation was encountered.

Humans↗

PubMed2026

EGFLAM Pathogenic Variants and Congenital Stationary Night Blindness.

IMPORTANCE: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches. OBJECTIVE: To describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families. DESIGN, SETTING AND PARTICIPANTS: This retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically. EXPOSURES: Complete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES). MAIN OUTCOMES AND MEASURES: The main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis. RESULTS: The series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina. CONCLUSION AND RELEVANCE: This case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.

Adolescent↗

PubMed2025

Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa.

PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss of rod and cone photoreceptors, leading to visual impairment and blindness. To date, to our knowledge, X-linked RP has been associated with variants in 3 genes (RPGR, RP2, and OFD1), whereas genetic defects at 3 loci (RP6, RP24, and RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP. METHODS: Participants were identified from cohorts of genetically unsolved male individuals affected by RP, who underwent genome sequencing, exome sequencing, or candidate gene screening via direct Sanger sequencing at 3 referral centers. Specifically, 2 probands were identified at the National Reference Centre for Rare Retinal Diseases (Paris, France), 2 at the Massachusetts Eye and Ear Hospital (Boston, MA), and 1 at the National Reference Centre for Inherited Sensory Diseases (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays. RESULTS: We identified 4 rare single-nucleotide variants in IDH3G (HGNC:5386), located at the RP34 locus on the X chromosome, and a complete gene deletion, in 5 unrelated male individuals affected with nonsyndromic RP. The variants segregated with the phenotype in all available family members. In all cases, the disease severity was intermediate. None had high myopia. IDH3G encodes the γ subunit of mitochondrial isocitrate dehydrogenase (IDH3), an enzyme involved in the citric acid cycle, which is expressed in the inner segments of photoreceptors. Variants in IDH3A and IDH3B, encoding the other subunits of IDH3, have already been associated with nonsyndromic autosomal recessive RP. Bioinformatic predictions and functional assays support a pathogenic role for the variants identified in this study, possibly through partial loss of enzymatic activity and mitochondrial function. CONCLUSION: Our findings suggest that variants in IDH3G are a novel cause of X-linked RP.

Humans↗