Clinician-Driven Reanalysis of Exome Sequencing Data From Patients With Inherited Retinal Diseases.

Importance: Despite advances in next-generation sequencing (NGS), a significant proportion of patients with inherited retinal disease (IRD) remain undiagnosed after initial genetic testing. Exome sequencing (ES) reanalysis in the clinical setting has been suggested as one method for improving diagnosis of IRD. Objective: To investigate the association of clinician-led reanalysis of ES data, which incorporates updated clinical information and comprehensive bioinformatic analysis, with the diagnostic yield in a cohort of patients with IRDs in Korea. Design, Setting, and Participants: This was a multicenter prospective cohort study involving 264 unrelated patients with IRDs, conducted in Korea between March 2018 and February 2020. Comprehensive ophthalmologic examinations and ES analyses were performed, and ES data were reanalyzed by an IRD specialist for single nucleotide variants, copy number variants, mobile element insertions, and mitochondrial variants. Data were analyzed from March to July 2023. Main Outcomes and Measures: Diagnostic rate of conventional bioinformatic analysis and clinician-driven ES reanalysis. Results: A total of 264 participants (151 [57.2%] male; mean [SD] age at genetic testing, 33.6 [18.9] years) were enrolled, including 129 patients (48.9%) with retinitis pigmentosa and 26 patients (9.8%) with Stargardt disease or macular dystrophy. Initial bioinformatic analysis diagnosed 166 patients (62.9%). Clinician-driven reanalysis identified the molecular cause of diseases in an additional 22 patients, corresponding to an 8.3-percentage point increase in diagnostic rate. Key factors associated with new molecular diagnoses included clinical phenotype updates (4 patients) and detection of previously overlooked variation, such as structural variants (9 patients), mitochondrial variants (3 patients), filtered or not captured variants (4 patients), and noncanonical splicing variants (2 patients). Among the 22 patients, variants in 7 patients (31.8%) were observed in the initial analysis but not reported to patients, while those in the remaining 15 patients (68.2%) were newly detected by the ES reanalysis. Conclusions and Relevance: In this cohort study, clinician-centered reanalysis of ES data was associated with improved molecular diagnostic yields in patients with IRD. This approach is important for uncovering missed genetic causes of retinal disease.

Two novel non-coding single nucleotide variants in the DNase1 hypersensitivity site of PRDM13 causing North Carolina macular dystrophy in Korea.

Purpose: Pathogenic variants in North Carolina macular dystrophy (NCMD) have rarely been reported in the East Asian population. Herein, we reported novel variants of NCMD in 2 Korean families. Methods: The regions associated with NCMD were analyzed with genome sequencing, and variants were filtered based on the minor allele frequency (0.5%) and heterozygosity. Non-coding variants were functionally annotated using multiple computational tools. Results: We identified two rare novel variants, chr6:g.99,598,914T>C (hg38; V17) and chr6:g.99,598,926G>A (hg38; V18) upstream of PRDM13 in families A and B, respectively. In Family 1, Grade 2 NCMD and a best-corrected visual acuity of 20/25 and 20/200 in the right and left eyes, respectively, were observed. In Family B, all affected individuals had Grade 1 NCMD with characteristic confluent drusen at the fovea and a best-corrected visual acuity of 20/20 in both eyes. These two variants are 10-22 bp downstream of the reported V10 variant within the DNase1 hypersensitivity site. This site is associated with progressive bifocal chorioretinal atrophy and congenital posterior polar chorioretinal hypertrophy and lies in the putative enhancer site of PRDM13. Conclusion: We identified two novel NCMD variants in the Korean population and further validated the regulatory role of the DNase1 hypersensitivity site upstream of PRDM13.

Coding and non-coding variants in the ciliopathy gene CFAP410 cause early-onset non-syndromic retinal degeneration.

Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. The implementation of next-generation sequencing in routine diagnostics, together with advanced clinical phenotyping including multimodal retinal imaging, have contributed to the increase of reports describing novel genotype-phenotype associations and phenotypic expansions. In this study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with syndromic recessive Jeune syndrome. The most common retinal phenotypes were cone-rod and rod-cone dystrophies, but the clinical presentations were unified by their early onset as well as the severe impact on central visual function. Twelve variants were detected (three pathogenic, seven likely pathogenic, two of uncertain significance), eight of which were novel. One deep intronic change, c.373+91A>G, led to the creation of a cryptic splice acceptor site in intron four, followed by the inclusion of a 200- base pair pseudoexon and subsequent premature stop codon formation. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Meta-analysis of all published and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.

Prognostic factors of first-onset optic neuritis based on diagnostic criteria and antibody status: a multicentre analysis of 427 eyes.

BACKGROUND: Optic neuritis (ON) prognosis is influenced by various factors including attack severity, underlying aetiologies, treatments and consequences of previous episodes. This study, conducted on a large cohort of first ON episodes, aimed to identify unique prognostic factors for each ON subtype, while excluding any potential influence from pre-existing sequelae. METHODS: Patients experiencing their first ON episodes, with complete aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing, and clinical data for applying multiple sclerosis (MS) diagnostic criteria, were enrolled. 427 eyes from 355 patients from 10 hospitals were categorised into four subgroups: neuromyelitis optica with AQP4 IgG (NMOSD-ON), MOG antibody-associated disease (MOGAD-ON), ON in MS (MS-ON) or idiopathic ON (ION). Prognostic factors linked to complete recovery (regaining 20/20 visual acuity (VA)) or moderate recovery (regaining 20/40 VA) were assessed through multivariable Cox regression analysis. RESULTS: VA at nadir emerged as a robust prognostic factor for both complete and moderate recovery, spanning all ON subtypes. Early intravenous methylprednisolone (IVMP) was associated with enhanced complete recovery in NMOSD-ON and MOGAD-ON, but not in MS-ON or ION. Interestingly, in NMOSD-ON, even a slight IVMP delay in IVMP by >3 days had a significant negative impact, whereas a moderate delay up to 7-9 days was permissible in MOGAD-ON. Female sex predicted poor recovery in MOGAD-ON, while older age hindered moderate recovery in NMOSD-ON and ION. CONCLUSION: This comprehensive multicentre analysis on first-onset ON unveils subtype-specific prognostic factors. These insights will assist tailored treatment strategies and patient counselling for ON.

Risk of central nervous system demyelinating attack or optic neuritis recurrence after pediatric optic neuritis in Korea.

PURPOSE: To investigate the rate of development of symptomatic central nervous system (CNS) demyelinating attacks or recurrent optic neuritis (ON) after the first episode of ON and its risk factors for Korean pediatric patients. METHODS: This multicenter retrospective cohort study included the patients under 18 years of age (n=132) diagnosed with ON without previous or simultaneous CNS demyelinating diseases. We obtained the clinical data including the results of neuro-ophthalmological examinations, magnetic resonance images (MRIs), antibody assays, and laboratory tests. We investigated the chronological course of demyelinating disease with respect to the occurrence of neurological symptoms and/or signs, and calculated the 5-year cumulative probability of CNS demyelinating disease or ON recurrence.  RESULTS: During the follow-up period (63.1±46.7 months), 18 patients had experienced other CNS demyelinating attacks, and the 5-year cumulative probability was 14.0±3.6%. Involvement of the extraorbital optic nerve or optic chiasm and asymptomatic lesions on the brain or spinal MRI at initial presentation were significant predictors for CNS demyelinating attack after the first ON. The 5-year cumulative probability of CNS demyelinating attack was 44.4 ± 24.8% in the AQP4-IgG group, 26.2±11.4% in the MOG-IgG group, and 8.7±5.9% in the double-negative group (P=0.416). Thirty-two patients had experienced a recurrence of ON, and the 5-year cumulative probability was 24.6±4.0%. In the AQP4-IgG group, the 5-year cumulative probability was 83.3±15.2%, which was significantly higher than in the other groups (P<0.001). CONCLUSIONS: A careful and multidisciplinary approach including brain/spinal imaging and antibody assay can help predict further demyelinating attacks in pediatric ON patients.

Comprehensive evaluation of ocular complications in atopic dermatitis: insights from a contemporary cohort study in Korean population.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with various systemic and ocular complications. This study aimed to investigate the prevalence, risk factors, and clinical characteristics of ocular complications in a cohort of Korean AD patients. METHODS: A retrospective review of medical records was conducted for AD patients who visited the dermatology and ophthalmology clinics at the same institution. Demographic data, clinical characteristics, and types of ocular complications were recorded. Logistic regression analysis was performed to identify factors associated with ocular complications. RESULTS: A total of 212 AD patients were included in the study. The intraocular complications had a prevalence of 1.9%, whereas ocular surface diseases were observed more frequently, with prevalence of 13.2%. Among the ocular complications, blepharitis was the most prevalent, followed by atopic keratoconjunctivitis. Subcapsular cataract, atrophic hole, and retinal detachment were also observed. The head and neck score in the Eczema Area and Severity Index (EASI) emerged as a significant predictor for intraocular complications, independent of age, gender, total EASI score, and family history. No significant association was found between total EASI score and ocular surface disease. CONCLUSION: This study provides insights into the prevalence and risk factors of ocular complications in Korean AD patients. The head and neck score in EASI was identified as a significant predictor for intraocular complications. These findings emphasize the importance of comprehensive evaluation and interdisciplinary care for AD patients, particularly in identifying and managing potential vision-threatening complications.

Efficacy of part-time patching in preventing recurrence after bilateral lateral rectus recession in children with intermittent exotropia.

BACKGROUND: This study evaluate the efficacy of part-time patching in preventing recurrence after bilateral lateral rectus recession (BLR) in patients with intermittent exotropia (IXT). METHODS: A total of 190 children aged 3-13 years who experienced recurrence after BLR for IXT and received part-time patching were retrospectively reviewed. The patching was prescribed for 2 h per day for more than 6 months. Patients who had a recurrence of 18 PD or more underwent reoperation. Changes in exodeviation and reoperation ratio after part-time patching were analyzed. RESULTS: A total of 34 patients (17.9%) received reoperation after part-time patching, and the reoperation ratio after 2 years was 20.3% as per the Kaplan-Meier survival analysis. Patients with a recurrence of 7 to 10 PD showed a significantly better effect compared to those with a recurrence of more than 10 PD (p < 0.001), and the reoperation ratio was also lower in the survival analysis (p = 0.004). The factor associated with reoperation in patients with part-time patching was the duration between the operation and the initiation of part-time patching (hazard ratio [HR] = 1.006, p = 0.002). CONCLUSIONS: Part-time patching was effective in maintaining the efficacy of surgery and delaying the need of reoperation after BLR. This effect was better in patients with a recurrence of ≤ 10 PD.

Neuro-Ophthalmic Adverse Events of COVID-19 Infection and Vaccines: A Nationwide Cohort Study.

Purpose: To evaluate the association of COVID-19 infection and vaccination with neuro-ophthalmic adverse events. Methods: In this nationwide population-based retrospective cohort study, 8,498,353 patients were classified into three groups: control, COVID-19 infection, and COVID-19 vaccination. We conducted separate analyses for the early phase (within 60 days) and late phases (61-180 days) to estimate the incidence rates and hazard ratio (HR) for each neuro-ophthalmic adverse event. The adverse events included in this analysis were optic neuritis, papilledema, ischemic optic neuropathy, third nerve palsy, fourth nerve palsy, sixth nerve palsy, facial palsy, nystagmus, ptosis, blepharospasm, anomalies of pupillary function, and Guillain-Barré syndrome/Miller Fisher syndrome (GBS/MFS). Results: Neuro-ophthalmic adverse events other than ptosis and GBS/MFS exhibited no significant increase after COVID-19, and their incidence was extremely low. The incidence rate of ptosis in both phases was significantly higher in patients administered COVID-19 vaccination (HR = 1.65 in the early phase and HR = 2.02 in the late phase) than in the control group. Additionally, BNT162b2 conferred a lower ptosis risk than ChAdOx1. GBS/MFS had a significantly higher incidence rate in the early phase (HR = 5.97) in patients with COVID-19 infection than in the control group. Conclusions: Ptosis was associated with COVID-19 vaccination, particularly with the ChAdOx1 vaccine, while GBS/MFS was associated with COVID-19 infection. In contrast, no association was found between other neuro-ophthalmic adverse events and COVID-19 infection or vaccination. These results may provide helpful insights for diagnosing and treating the neuro-ophthalmological adverse events after COVID-19.

Bickerstaff's brainstem encephalitis: a rare case of neurologic complication in Ulcerative Colitis.

Bickerstaff's brainstem encephalitis is a rare autoimmune disorder that presents with ataxia, ophthalmoplegia, disturbance of consciousness and quadriplegia. A 45-year-old man with a history of ulcerative colitis (UC) taking mesalazine (5-aminosalicylic acid) visited the emergency room presenting with ataxia, ophthalmoplegia and a progressively worsening cognitive impairment. Cerebrospinal fluid analysis showed mild elevation in protein and white blood cell count and increased intracranial pressure. Anti-GQ1b autoantibodies were found positive in the patient's serum and contrast-enhanced brain magnetic resonance imaging showed diffuse leptomeningeal enhancement and pontine lesions. Based on these findings and the patient's clinical course and history, he was diagnosed with Bickerstaff's brainstem encephalitis. Mesalazine was discontinued and high-dose steroid pulse therapy was started, followed by intravenous immunoglobulin, which resulted in gradual improvement of the neurologic symptoms. When an ulcerative colitis patient presents with progressive cognitive impairment, quadriplegia and disturbance of consciousness and gait, Bickerstaff brainstem encephalitis should be considered in the differential diagnosis and prompt immunotherapy may lead to favorable prognosis.

Clinical and genetic features of Koreans with retinitis pigmentosa associated with mutations in rhodopsin.

Purpose: To investigate the clinical features, natural course, and genetic characteristics of Koreans with rhodopsin-associated retinitis pigmentosa (RHO-associated RP). Design: We conducted a retrospective, multicenter, observational cohort study. Participants: We reviewed the medical records of 42 patients with RHO-associated RP of 36 families who visited 4 hospitals in Korea. Methods: Patients with molecular confirmation of pathogenic variants of the RHO gene were included. The patients were divided into two subgroups: the generalized and sector RP groups. A central visual field of the better-seeing eye of <10° or a best-corrected visual acuity of the better-seeing eye <20/40 indicated the progression to late-stage RP. Results: The mean age at which symptoms first appeared was 26.3 ± 17.9 years (range: 8-78 years), and the mean follow-up period was 80.9 ± 68.7 months (range: 6-268 months). At the last follow-up visit, the generalized RP group showed a significantly higher rate of visual field impairment progression to late-stage RP than that of the sector RP group (22 of 35 [62.9%] vs. 0 of 7 [0.0%], p = 0.003). No cases in the sector RP group progressed to generalized RP. Best-corrected visual acuity deterioration to late-stage RP was observed only in the generalized RP group (13 of 35 patients; 37.1%), whereas no deterioration was observed in the sector RP group. We identified 16 known and three novel RHO mutations, including two missense mutations (p.T108P and p.G121R) and one deletion mutation (p.P347_A348del). The pathogenic variants were most frequently detected in exon 1 (14 of 36 [38.9%]). The most common pathogenic variants were p.P347L and T17M (5 of 36 [13.9%] families). Among 42 patients of 36 families, 35 patients of 29 families (80.6%) presented with the generalized RP phenotype, and seven patients of seven families (19.4%) presented with the sector RP phenotype. Three variants (p.T17M, p.G101E, and p.E181K) presented with both the generalized and sector RP phenotypes. Conclusion: This multicenter cohort study provided information on the clinical and genetic features of RHO-associated RP in Koreans. It is clinically important to expand the genetic spectrum and understand genotype-phenotype correlations to ultimately facilitate the development of gene therapy.

Clinical and Genetic Findings in Korean Patients with Choroideremia.

PURPOSE: We share and analyze the clinical presentations and genotypes of Korean male patients and female carriers who visited our clinic. METHODS: Six male patients and three female carriers with comprehensive ophthalmic examinations and next-generation sequencing were included. Detailed clinical features were identified using visual field (VF) test and multimodal imaging including color fundus photography, fundus autofluorescence (FAF), and optical coherence tomography (OCT). RESULTS: Six male patients were diagnosed with choroideremia at the median age of 25 years. Before genetic testing, three patients (50.0%) were clinically diagnosed with choroideremia, while the other three patients (50.0%) with retinitis pigmentosa. Patients showed different types of hemizygous CHM variants, including two nonsense variants, c.715C>T:p.(Arg239*) and c.799C>T:p.(Arg267*); two frameshift variants, c.1584_1587del:p.(Val529Hisfs*7) and c.403_404del:p.(Asp135Phefs*9); one splicing variant c.1511-28_1511-2del; and one exon 2-8 duplication. The latter three variants were novel. Two female carriers had heterozygous exon 2-8 duplication and the other one female carrier had heterozygous nonsense variant c.715C>T:p. (Arg239*). Fundus showed diffuse yellow-whitish scleral reflex and granular pigmented lesions. FAF showed multiple patchy hypofluorescence lesions, sparing macula. OCT showed thinning of outer nuclear layer, ellipsoid zone, retinal pigment epithelium layer, choroid thickness, interlaminar bridges, outer retinal tubulations, and microcysts in the inner nuclear layer. VF showed ring scotoma pattern with small amount of remaining central field. Asymptomatic female carriers showed variable fundus findings and mild changes in OCT. CONCLUSIONS: A detailed description of the genotypes with three novel mutations and phenotypes of six choroideremia patients and three CHM mutation female carriers are presented.

Genotypic Profile and Clinical Characteristics of CRX-Associated Retinopathy in Koreans.

This study aimed to investigate the clinical characteristics of Korean patients with retinal dystrophy associated with pathogenic variants of cone rod homeobox-containing gene (CRX). We retrospectively enrolled Korean patients with CRX-associated retinal dystrophy (CRX-RD) who visited two tertiary referral hospitals. Pathogenic variants were identified using targeted panel sequencing or whole-exome sequencing. We analyzed clinical features and phenotypic spectra according to genotype. Eleven patients with CRX-RD were included in this study. Six patients with cone-rod dystrophy (CORD), two with macular dystrophy (MD), two with Leber congenital amaurosis (LCA), and one with retinitis pigmentosa (RP) were included. One patient (9.1%) had autosomal recessive inheritance, and the other ten patients (90.9%) had autosomal dominant inheritance. Six patients (54.5%) were male, and the mean age of symptom onset was 27.0 ± 17.9 years. At the first presentation, the mean age was 39.4 ± 20.6 years, and best-corrected visual acuity (BCVA) (logMAR) was 0.76 ± 0.90 in the better eye. Negative electroretinography (ERG) was observed in seven (63.6%) patients. Nine pathogenic variants were identified, including two novel variants, c.101-1G>A and c.898T>C:p.(*300Glnext*118). Taken together with the variants reported in prior studies, all variants within the homeodomain are missense variants, whereas most variants downstream of the homeodomain are truncating variants (88%). The clinical features of pathogenic variants within the homeodomain are either CORD or MD with bull's eye maculopathy, whereas variants downstream of the homeodomain cause more diverse phenotypes, with CORD and MD in 36%, LCA in 40%, and RP in 24%. This is the first case series in Korea to investigate the CRX-RD genotype-phenotype correlation. Pathogenic variants downstream of the homeodomain of the CRX gene are present as RP, LCA, and CORD, whereas pathogenic variants within the homeodomain are mainly present as CORD or MD with bull's eye maculopathy. This trend was similar to previous genotype-phenotype analyses of CRX-RD. Further molecular biologic research on this correlation is required.

Correlation between bilateral lateral rectus muscle recession and myopic progression in children with intermittent exotropia.

Although several studies have reported about the relationship between the surgical correction of intermittent exotropia and myopic progression, it remains unclear, unlike the relationship between esotropia and hyperopia. Thus, this retrospective case control study evaluated the impact of bilateral lateral rectus recession in intermittent exotropia on myopic progression. This study included 388 patients with intermittent exotropia. The refractive errors and degree of exodeviation at each follow up period were analyzed. The rate of myopic progression was -0.46 ± 0.62 diopter (D)/year in patients who underwent surgery and -0.58 ± 0.78 D/year in patients who did not, with no significant difference between them (p = 0.254). Patients who had recurrences of more than 10 prism diopters were compared with patients who did not have. The rate of myopic progression was -0.57 ± 0.72 D/year in the recurrent group and -0.44 ± 0.61 D/year in the non-recurrent group, with no significant difference between them (p = 0.237). Patients with fast myopic progression had more recurrence than patients with slow progression (p = 0.042). Moreover, recurrence had a positive correlation with fast myopic progression (OR = 2.537, p = 0.021). Conclusively, the surgical correction of intermittent exotropia did not influence myopic progression.

Voretigene Neparvovec for the Treatment of RPE65-associated Retinal Dystrophy: Consensus and Recommendations from the Korea RPE65-IRD Consensus Paper Committee.

Mutations in the RPE65 gene, associated with Leber congenital amaurosis, early-onset severe retinal dystrophy, and retinitis pigmentosa, gained growing attention since gene therapy for patients with RPE65-associated retinal dystrophy is available in clinical practice. RPE65 gene accounts for a very small proportion of patients with inherited retinal degeneration, especially Asian patients. Because RPE65-associated retinal dystrophy shares common clinical characteristics, such as early-onset severe nyctalopia, nystagmus, low vision, and progressive visual field constriction, with retinitis pigmentosa by other genetic mutations, appropriate genetic testing is essential to make a correct diagnosis. Also, fundus abnormalities can be minimal in early childhood, and the phenotype is highly variable depending on the type of mutations in RPE65-associated retinal dystrophy, which makes a diagnostic difficulty. The aim of this paper is to review the epidemiology of RPE65-associated retinal dystrophy, mutation spectrum, genetic diagnosis, clinical characteristics, and voretigene neparvovec, a gene therapy product for the treatment of RPE65-related retinal dystrophy.

Clinical and Genetic Features of Korean Patients with Achromatopsia.

This multicenter study aimed to characterize Korean patients with achromatopsia. The patients' genotypes and phenotypes were retrospectively evaluated. Twenty-one patients (with a mean age at the baseline of 10.9 years) were enrolled and followed up for a mean of 7.3 years. A targeted gene panel or exome sequencing was performed. The pathogenic variants of the four genes and their frequencies were identified. CNGA3 and PDE6C were equally the most prevalent genes: CNGA3 (N = 8, 38.1%), PDE6C (N = 8, 38.1%), CNGB3 (N = 3, 14.3%), and GNAT2 (N = 2, 9.5%). The degree of functional and structural defects varied among the patients. The patients' age exhibited no significant correlation with structural defects. During the follow-up, the visual acuity and retinal thickness did not change significantly. In CNGA3-achromatopsia patients, a proportion of patients with a normal foveal ellipsoid zone on the OCT was significantly higher than that of patients with other causative genes (62.5% vs. 16.7%; p = 0.023). In PDE6C-achromatopsia patients, the same proportion was significantly lower than that of patients with other causative genes (0% vs. 58.3%; p = 0.003). Korean patients with achromatopsia showed similar clinical features but a higher prevalence of PDE6C variants than those of other ethnic groups. The retinal phenotypes of the PDE6C variants were more likely to be worse than those of other genes.

Retinal Proteome Analysis Reveals a Region-Specific Change in the Rabbit Myopia Model.

Uncovering region-specific changes in the myopic retina can provide clues to the pathogenesis of myopia progression. After imposing form deprivation myopia in the right eye of 6-week-old rabbits, we investigated the proteome profile of each retinal region (central, mid-periphery, and far-periphery retina), using accurate high-resolution mass spectrometry. Protein expression was analyzed using gene ontology and network analysis compared with that of the control, the left eyes. Among 2065 proteins detected from whole retinal samples, 249 differentially expressed proteins (DEPs) were identified: 164 DEPs in the far-periphery, 39 in the mid-periphery, and 83 in the central retina. In network analysis, the far-periphery retina showed the most significant connectivity between DEPs. The regulation of coagulation was the most significant biological process in upregulated DEPs in the far-periphery retina. Proteasome was the most significant Kyoto Encyclopedia of Genes and Genomes pathway in downregulated DEPs in the central retina. Antithrombin-III, fibrinogen gamma chain, and fibrinogen beta chain were identified as hub proteins for myopia progression, which were upregulated in the far-periphery retina. Proteomic analysis in this study suggested that oxidative stress can be the primary pathogenesis of myopia progression and that the far-periphery retina plays a role as the key responder.

The importance of genome sequencing: unraveling SSBP1 variant missed by exome sequencing.

BACKGROUND: Single-stranded DNA-binding protein 1 (SSBP1) plays an essential role in mitochondrial DNA (mtDNA) replication and maintenance, as well as development of retina. Here, we describe the clinical findings and genetic basis of a family with two members affected with bilateral optic atrophy. MATERIALS AND METHODS: Clinical data were retrospectively collected from an electronic medical record system. Genetic results were obtained using exome sequencing (ES) and genome sequencing (GS). RESULTS: A 36-year-old man presented with low vision in both eyes since early childhood, with a best-corrected visual acuity of 20/500 in both eyes. He exhibited generalized optic atrophy and diffuse retinal nerve fiber layer thinning without retinal degeneration in both eyes. The family history was consistent with autosomal dominant traits. ES was performed; however, we did not identify any pathogenic variants in the known dominant optic atrophy genes. Subsequently, GS was performed, and it revealed a novel heterozygous c.364A>G p.(Lys122Glu) variant in SSBP1. In silico prediction supported it as deleterious, while segregation analysis detected it in his affected mother and his unaffected sister. No foveopathy or retinal degeneration was observed in the patient's family members. CONCLUSIONS: We report a novel pathogenic heterozygous SSBP1 variant in a family with autosomal dominant optic atrophy and incomplete penetrance. Furthermore, we demonstrated that GS is advantageous over ES even for the discovery of coding variants, providing uniform coverage. Therefore, GS should be emphasized to improve the molecular diagnostic rate of inherited optic neuropathy.

Expanding SPG7 dominant optic atrophy phenotype: Infantile nystagmus and optic atrophy without spastic paraplegia.

Spastic paraplegia is a neurodegenerative disorder characterized by progressive leg weakness and spasticity due to degeneration of corticospinal axons. SPG7 encodes paraplegin, and pathogenic variants in the gene cause hereditary spastic paraplegia as an autosomal recessive trait. Various ophthalmological findings including optic atrophy, ophthalmoplegia, or nystagmus have been reported in patients with spastic paraplegia type 7. We report a 15-year-old male patient with a novel heterozygous variant, c.1224T>G:p.(Asp408Glu) in SPG7 (NM_003119.3) causing early onset isolated optic atrophy and infantile nystagmus prior to the onset of neurological symptoms. Therefore, SPG7 should be considered a cause of infantile nystagmus with optic atrophy.

Factors Related to Axial Length Elongation in Myopic Children Who Received 0.05% Atropine Treatment.

Purpose: To evaluate the longitudinal changes of axial length (AL) and factors associated with AL growth in myopic children receiving 0.05% atropine. Methods: This single-center retrospective study included children aged 4-13 years with myopia of at least -0.5 diopters (D) treated with 0.05% atropine eye drops from November 2016 to May 2021. Predictive factors for AL change were evaluated using linear mixed models. Results: Among 109 patients (218 eyes), 58 (53.2%) were male and the mean age at treatment was 8.5 ± 2.0 years. At baseline measurement, the mean spherical equivalent was -4.05 ± 2.34 diopters (D), and AL was 25.00 ± 0.97 mm. The mean follow-up duration was 25.4 (12-58) months, and the mean AL elongation was 0.23 ± 0.17 mm/year during the follow-up periods. AL shortening of ≥0.05 mm at subsequent visit occurred in 18 patients (26 eyes). The mean AL change in the group without initial AL shortening was statistically larger than that in the group with initial AL shortening (0.26 ± 0.16 mm/year vs. 0.02 ± 0.17 mm/year, P < 0.001). In linear mixed model, the age at atropine treatment and initial AL shortening were significantly associated with respect to AL growth (beta coefficient: -0.032 and -0.122, respectively, P < 0.001 for both). Conclusions: Our study found that older age and initial AL shortening are predictors of favorable response after 0.05% atropine treatment. Children with AL shortening at initial subsequent visit may be associated with good long-term response, and younger children may require higher concentration of atropine for optimal response.