Ophthalmic Genetics最新文献

{"title":"A genotype to phenotype relationship of exudative vitreoretinopathy in Loeys-Dietz syndrome due to a pathogenic variant in <i>TGFBR2</i>.","authors":"Mark Lindquist, Viridiana Hernandez-Lopez, Debarshi Mustafi","doi":"10.1080/13816810.2025.2565633","DOIUrl":"https://doi.org/10.1080/13816810.2025.2565633","url":null,"abstract":"<p><strong>Introduction: </strong>Loeys-Dietz syndrome (LDS) is a rare autosomal dominant connective tissue disorder most commonly due to pathogenic variants in the transforming growth factor beta receptor genes <i>TGFBR1</i> and <i>TGFBR2</i>. There have been reports of a few sporadic cases of LDS patients exhibiting a vitreoretinopathy phenotype due to pathogenic variants in the TGFBR2 gene.</p><p><strong>Case presentation: </strong>We report a 13-year-old female with LDS who harbored a de novo pathogenic missense variant (c.1582C>T, p.Arg528Cys) in <i>TGFBR2</i>. She presented with reduced visual acuity in the right eye due to a vitreous hemorrhage. Fluorescein angiography identified neovascularization in the right eye with peripheral avascular retina in both eyes. These phenotypic features were similar to those seen in familial exudative vitreoretinopathy (FEVR). Intravitreal anti-VEGF treatment in the right eye led to visual improvement, followed by laser photocoagulation of the peripheral retina of both eyes to mitigate future complications.</p><p><strong>Discussion: </strong>This is the second reported case of a missense variant at the amino acid residue 528 (Arg528) of <i>TGFBR2</i> that results in a FEVR-like phenotype in a LDS patient. In silico protein prediction and machine learning analyses of the affected region of the <i>TGFBR2</i> protein suggest this missense variant disrupts the protein kinase domain. We hypothesize this change influences the Wnt/beta-catenin pathway, leading to abnormal retinal vasculogenesis.</p><p><strong>Conclusions: </strong>This case highlights the importance of a genotype to phenotype relationship in LDS and suggests that certain variants in <i>TGFBR2</i> may predispose to vitreoretinopathy. Recognition of this is important as timely anti-VEGF and laser intervention can limit visual threatening complications.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-4"},"PeriodicalIF":1.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new genotype of the <i>IDH3A</i> gene causes retinitis pigmentosa, generating functional dyschromatopsia from early childhood.","authors":"Nuria Rosell-Saiz, Antonio Sierra-Rivera, Jordi Tortosa-Carreres, Clara Monferrer-Adsuara, Javier Montero-Hernández, Carmen Espinós, Raquel Rodríguez-López","doi":"10.1080/13816810.2025.2563909","DOIUrl":"https://doi.org/10.1080/13816810.2025.2563909","url":null,"abstract":"<p><strong>Introduction: </strong>We report the case of a 42-year-old Venezuelan woman with childhood-onset autosomal recessive retinitis pigmentosa type 90 (RP90), presenting an unusual and distinctive clinical phenotype characterized by macular pseudocoloboma, very early-onset acquired color vision disorder progressing to severe functional dyschromatopsia, and early-onset severe posterior subcapsular cataracts. Her affected brother exhibited a similar phenotype, while her parents and the other two siblings remained unaffected.</p><p><strong>Methods and results: </strong>Massive parallel sequencing identified two novel <i>IDH3A</i> variants: c.127G>T (chr15:78449926 G>T; no dbSNP entry) and c.419T>C (chr15:78454052T>C; no dbSNP entry), in compound heterozygosity and confirmed to be in <i>trans</i> location. Both missense variants, absent from population databases, were predicted to be deleterious by multiple <i>in silico</i> tools and are located in critical domains involved in enzymatic complex stability, catalytic activity and subunit interactions.</p><p><strong>Conclusions: </strong>This case reinforces the association between <i>IDH3A</i> mutations and <i>RP90</i>, corroborates key phenotypic features described in limited published reports-the presence of macular pseudocoloboma-and expands the mutational spectrum of the gene. Moreover, it highlights the role of mitochondrial metabolism in photoreceptor degeneration and proposes a link between them. Our findings underscore the need for functional studies to elucidate the pathogenic mechanisms underlying <i>IDH3A</i>-related retinopathies.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-6"},"PeriodicalIF":1.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>ADAMTSL4</i> ectopia lentis associated with Poland syndrome: a case report.","authors":"Daniel Cool, Shuan Dai, Allister Lee","doi":"10.1080/13816810.2025.2565650","DOIUrl":"https://doi.org/10.1080/13816810.2025.2565650","url":null,"abstract":"<p><strong>Background: </strong>Poland Syndrome is primarily characterized by musculoskeletal anomalies, such as unilateral absence of the sternocostal head of the pectoralis major. Ocular associations with Poland syndrome are rare, and <i>ADAMTSL4</i> mutations, typically linked to autosomal recessive ectopia lentis, have not been previously associated with this condition.</p><p><strong>Case: </strong>We describe a 20-month-old female with left-sided Poland syndrome who presented with intermittent right eye pain and a history of progressive corneal clouding. Examination revealed bilateral ectopia lentis, buphthalmos, and elevated intraocular pressure. Genetic testing identified a homozygous <i>ADAMTSL4</i> variant (c.767_786del20), a novel association with Poland syndrome. The patient underwent successful bilateral lensectomy and anterior vitrectomy, and management of glaucoma was initiated. Her monochorionic diamniotic (MCDA) twin, also harboring the same <i>ADAMTSL4</i> mutation, exhibited bilateral ectopia lentis and underwent surgical intervention.</p><p><strong>Discussion: </strong>This report is the first to document an association between Poland syndrome and an <i>ADAMTSL4</i> mutation, potentially suggesting a shared underlying defect in microfibril assembly. These findings expand our understanding of the genetic and developmental complexities of Poland syndrome and underscore the importance of early ophthalmological evaluation in such patients.</p><p><strong>Conclusion: </strong>This case highlights the significance of genetic and ocular investigations in Poland syndrome, contributing to knowledge on its broader phenotypic spectrum and potential genetic etiologies. Further research is warranted to elucidate the role of <i>ADAMTSL4</i> in microfibril-related anomalies.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-4"},"PeriodicalIF":1.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal imaging and electrophysiological features in bradyopsia associated with homozygous variants (c.895T>C) in Regulator of G-protein Signaling 9 (<i>RGS9</i>).","authors":"Grace A Borchert, Rachael C Heath Jeffery, Sian Sperring, Morag Shanks, Jennifer Whitfield, Penny Clouston, Tina Lamey, Jennifer A Thompson, Danial Roshandel, Enid S Chelva, Charles Cottriall, Kanmin Xue, Samantha R De Silva, Jasmina Cehajic-Kapetanovic, Robert E MacLaren, Terri McLaren, Andrea H Nemeth, Susan M Downes, Fred K Chen","doi":"10.1080/13816810.2025.2554660","DOIUrl":"10.1080/13816810.2025.2554660","url":null,"abstract":"<p><strong>Purpose: </strong>To report multimodal imaging findings and natural history of clinical features in two probands with bradyopsia harboring homozygous variants (c.895T>C) in Regulator of G-protein Signaling 9 (RGS9).</p><p><strong>Methods: </strong>Ophthalmic history, clinical examination, fundus autofluorescence (FAF), optical coherence tomography (OCT), microperimetry, flood-illuminated adaptive optics (AO) imaging, and electroretinogram (ERG) were obtained.</p><p><strong>Results: </strong>A 37-year-old male and a 67-year-old female from non-consanguineous parents had normal fundus examination, FAF, and OCT. ERGs for the male case between the age of 4 and 38 years showed no progression. Both probands had flat International Society for Clinical Electrophysiology of Vision (ISCEV) Standard full-field ERG light-adapted (LA) responses but dark-adapted (DA) red x-wave and S-cone responses were present. DA 30 Hz flicker was present after 2 but not after 10 seconds. The reduced amplitude and b:a ratio of the DA10 response improved with increasing interstimulus interval. AO and microperimetry demonstrated preservation of foveal cone density and subnormal retinal sensitivity, respectively. Both measures remained stable over 3 years. The c.895T>C variant was classified as pathogenic.</p><p><strong>Conclusions: </strong>Bradyopsia associated with homozygous RGS9 c.895T>C variants is characterized by normal retinal structure but subnormal macular sensitivity. Extended ERG protocols can be used to confirm delayed phototransduction recovery.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-8"},"PeriodicalIF":1.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mutational landscape of hereditary retinoblastoma and genotype-phenotype associations in Lebanon.","authors":"Nada Assaf, Youssef Zougheib, Raphah Borghol, Christiane Al-Haddad","doi":"10.1080/13816810.2025.2554659","DOIUrl":"10.1080/13816810.2025.2554659","url":null,"abstract":"<p><strong>Background: </strong>Retinoblastoma is the most common intraocular tumor of childhood. In Lebanon, its incidence is reported at 3.6 per million person-years. This study aimed to characterize the spectrum of RB1 variants in hereditary retinoblastoma and explore genotype-phenotype associations in a Lebanese cohort.</p><p><strong>Methods: </strong>A retrospective chart review was conducted on retinoblastoma patients enrolled in the Children's Cancer Institute at the American University of Beirut Medical Center from 2012 to 2022. Genetic data (RB1 sequencing and karyotype), clinical characteristics, imaging, treatment, and outcomes were collected and compared between hereditary and sporadic cases, and across different variant types.</p><p><strong>Results: </strong>A total of 47 patients underwent genetic testing; 63% had hereditary retinoblastoma with 23 patients carrying single nucleotide changes, including four novel mutations, 3 patients with submicroscopic deletions/duplications, and 3 with deletion 13q syndrome. Nonsense mutations were most frequent (52.2%), followed by frameshift and splice-site alterations. Bilaterality was significantly associated with hereditary disease (85.7% vs. 21.1%, <i>p</i> < 0.001), and more common among Syrian patients (<i>p</i> = 0.04). Median age at diagnosis was younger in the hereditary group, although not statistically significant. Enucleation rates (57.1% vs. 78.9%) and vision outcomes were similar across groups (<i>p</i> > 0.05). No significant differences in treatment outcomes were found among different variant types. Among the 3 patients with deletion 13q, two exhibited severe psychomotor and developmental delays.</p><p><strong>Conclusion: </strong>Hereditary retinoblastoma accounted for 63% of cases, with 23 pathogenic variants including four novel ones. Bilaterality and Syrian nationality were significantly associated with RB1 positivity. This study underscores the importance of comprehensive RB1 genetic testing in improving diagnostic accuracy, guiding treatment decisions, and supporting genetic counselling, particularly in non-Western populations.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-6"},"PeriodicalIF":1.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating motile ciliopathies in a pediatric case of an abnormal optic nerve head.","authors":"Chioma Amuzie, Benjamin R Lin, Lauren Hucko, Serena Shah, Catherin I Negron, Craig A McKeown, Audina M Berrocal","doi":"10.1080/13816810.2025.2555469","DOIUrl":"10.1080/13816810.2025.2555469","url":null,"abstract":"<p><strong>Introduction: </strong>A congenital optic nerve head anomaly (CONHA) is an umbrella term for structurally abnormal optic nerve heads present at birth which may lead to vision loss. The potential roles of motile and non-motile ciliopathies in this process are not well understood. This report describes a pediatric case of CONHA and implicates a motile ciliopathy in a possible mechanism that affects embryogenesis of the optic nerve head.</p><p><strong>Case presentation: </strong>A 21-month-old male with a normal prenatal and postnatal course, past medical history of recurrent upper and lower airway infections, and no known ocular history was referred by a community ophthalmologist for evaluation of a dysplastic optic disc. After the initial visit, fundus examination at a subsequent EUA revealed a hypoplastic macula and an anomalous nerve. Evaluation by a pulmonologist at 32 months due to multiple airway infections revealed atopic dermatitis and moderate persistent asthma. Primary ciliary dyskinesia was ruled out.</p><p><strong>Discussion: </strong>We theorize that this patient's fundus and systemic findings have a similar etiology. Differentiation of primary cilia on airway epithelial cells is known to produce motile cilia. We hypothesize that insults to a common cell may lead to disruption of three downstream pathways in our patient. The first line resulted in an atopic profile due to a disruption of motile ciliogenesis and mucociliary clearance. Second, disruption of primary cilia within the Sonic hedgehog pathway, a key regulator of neuronal development, may have resulted in a CONHA. Finally, the presence of abnormal primary cilia may have led to retinal dysplasia.</p><p><strong>Conclusion: </strong>Linking systemic and ophthalmic findings can provide more insight into the role of motile cilia in other fundus conditions, allowing for targeted interventions. Thus, future research and gene therapy can work to prevent, or slow down, severe vision loss.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-5"},"PeriodicalIF":1.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trio exome sequencing of an optic nerve hypoplasia cohort reveals evidence for polygenic architecture.","authors":"Jennifer G Aparicio, Kevin Stachelek, Pamela Garcia-Filion, Brianne Brown, Carly Stewart, David W Craig, Wenhui Laura Li, David Cobrinik, Mark Borchert","doi":"10.1080/13816810.2025.2540400","DOIUrl":"https://doi.org/10.1080/13816810.2025.2540400","url":null,"abstract":"<p><strong>Background: </strong>Optic nerve hypoplasia (ONH), the leading congenital cause of permanent blindness, is characterized by a retinal ganglion cell (RGC) deficit at birth and frequently associated neurologic and endocrine abnormalities. Multifactorial developmental events are hypothesized to underlie ONH; however, environmental influences are unclear, and genetic causes are under-investigated.</p><p><strong>Methods: </strong>To identify monogenic, disease-causing variants among ONH patients, exomes from 34 ONH subjects and their parents were sequenced and rare variants identified. Inheritance-modelled variants were evaluated using population frequency, pathogenicity predictions, and mutational constraint metrics. Variants with the strongest genetic effect lacked evidence that they are monogenic and causal. All rare variants were filtered using mutational constraint metrics and pathogenicity predictions. The resultant variant-harboring genes were examined for recurrence within the cohort, gene ontology over-representation, RGC expression, and coincidence with neuro developmental disorder (NDD), autism, and previously proposed ONH genes.</p><p><strong>Results: </strong>Mutationally constrained genes with potentially pathogenic mutations were enriched in gene ontologies related to neuro developmental processes, were expressed in RGCs at significantly higher levels than random exome variant genes, and were enriched in autism and NDD-associated genes. Including the genes with strong genetic effect variants, these analyses call attention to 161 genes with potentially pathogenic variants that may contribute polygenic risk for ONH.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-13"},"PeriodicalIF":1.0,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuro-ophthalmic complications of endosteal hyperostosis, Worth type: the importance of ophthalmic monitoring.","authors":"Aisling Higham, Laura M Watts, Dipesh Rao, Paul Wordsworth, Darius Hildebrand, David Johnson, Deborah Shears","doi":"10.1080/13816810.2025.2535985","DOIUrl":"https://doi.org/10.1080/13816810.2025.2535985","url":null,"abstract":"<p><p>Disorders of bone formation or resorption affecting the cranium can lead to ophthalmic complications. We describe a family with Worth endosteal hyperostosis (WEH), an autosomal dominant condition characterized by mandibular overgrowth and cortical thickening of long bones. Although traditionally considered benign, we report significant neuro-ophthalmic complications in this kindred.This retrospective case series examines a two-generation family of three siblings and their mother, all with clinical features of WEH and a confirmed lipoprotein-related protein 5 (<i>LRP5)</i> gene mutation. A literature review is also included.The proband was diagnosed with WEH after an incidental finding of dense bones on a chest x-ray at age 16, with no neurological complications. However, her three affected children developed papilledema due to elevated intracranial pressure, requiring calvarial expansion. Computed tomography imaging revealed calvarial thickening and late-onset sagittal synostosis in two individuals. In two cases, intracranial hypertension was detected only after routine ophthalmic monitoring revealed papilledema. All had successful outcomes with resolution of papilledema following surgery.Here, we show that WEH can be associated with serious and late onset neuro-ophthalmic manifestations and secondary sagittal synostosis. We recommend regular ophthalmic review to facilitate early detection of potential complications, as part of the multidisciplinary care.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-4"},"PeriodicalIF":1.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A survey of genotypes associated with Leber congenital amaurosis and early-onset severe retinal degeneration identified in a Singaporean patient cohort.","authors":"Saadia Z Farooqui, Mathieu Quinodoz, Tien-En Tan, Rachael W C Tang, Choi Mun Chan, Ranjana Mathur, Li Yu Chen, Joey S Z Poh, Audrey W L Chia, Yasmin Bylstra, Weng Khong Lim, Carlo Rivolta, Beau J Fenner","doi":"10.1080/13816810.2025.2550693","DOIUrl":"https://doi.org/10.1080/13816810.2025.2550693","url":null,"abstract":"<p><strong>Purpose: </strong>Leber congenital amaurosis (LCA) and early-onset severe retinal degeneration (EOSRD) are inherited retinal diseases (IRDs) characterized by visual impairment beginning in infancy or childhood. This study aimed to describe the clinical and genetic characteristics of the first prospectively enrolled Singaporean patient cohort with disease-causing variants in genes associated with LCA, EOSRD, or related early-onset phenotypes.</p><p><strong>Methods: </strong>Thirty-four patients from 30 families were prospectively recruited and underwent comprehensive clinical and genetic evaluation. Phenotypic classification and genotypic distribution were analyzed and compared with previously reported cohorts.</p><p><strong>Results: </strong>Of the 34 patients, 24 presented with typical phenotypes of LCA (<i>n</i> = 12) or EOSRD (<i>n</i> = 11). Among the remaining cases carrying genotypes usually linked to LCA, 7 were diagnosed with retinitis pigmentosa, 3 with cone dystrophy, and 1 with macular dystrophy. The most frequently implicated gene was <i>CRB1</i>, detected in 8 families (26.7%), followed by <i>RDH12</i> (16.7%), and <i>CEP290</i> and <i>NMNAT1</i> (10% each). This genetic distribution differs from those reported in Western populations. Clinical phenotypes were heterogeneous with respect to disease course, macular involvement, retinal structural alterations, and residual photoreceptor function.</p><p><strong>Conclusions: </strong>This study represents the first report of a genetically confirmed cohort of LCA and EOSRD patients from Southeast Asia. The findings highlight a distinct genotypic spectrum compared with Western populations and underscore the extensive clinical heterogeneity of early-onset IRDs. These data provide a valuable foundation for patient stratification and planning of future gene therapy trials in the region.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-9"},"PeriodicalIF":1.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Importance of genome reference and population datasets for annotation and prioritization of disease-causing variants in inherited retinal diseases.","authors":"Stefan T Stafie, Mark Lindquist, Samuel Kusher-Lenhoff, Kenji Nakamichi, Debarshi Mustafi","doi":"10.1080/13816810.2025.2544639","DOIUrl":"https://doi.org/10.1080/13816810.2025.2544639","url":null,"abstract":"<p><p>In an era of expanding sequencing technologies, increased variant identification requires assignment of potential functional impact to prioritize those that may be disease-causing. In this data note, we demonstrate the importance of using a refined human genome reference assembly and more diverse and curated population-based databases in guiding functional annotation of variants identified in inherited retinal disease (IRD) genes. We compared variant characteristics extracted from Genome Aggregation Database (gnomAD) population data extracted for 372 IRD disease genes from versions 3.1.2 (v3) and 4.1.0 (v4), which are aligned to the most recent Genome Reference Consortium Human Build 38 (GRCh38) as well as version 2.1.1 (v2), aligned to the previous GRCh37 build. Transformation of the Variant Effector Prediction (VEP), Combined Annotation Dependent Depletion (CADD) scores, and ClinVar pathogenicity annotations were used to generate receiver-operating characteristic (ROC) curves to calculate area under the curve (AUC) and area under the precision-recall curve (AUPRC). Comparisons of variant prediction by ClinVar designation showed that with improved functional annotation, the AUC climbs to 0.99 and AUPRC is 0.98 in differentiating pathogenic variants from nonpathogenic when using the most recent genome build and population database. More diverse population data allow for identification of rare variants and the incorporation of variant annotation metrics provides greater insight into pathogenicity parameters of IRD variants. This data note provides empirical evidence to adopt the newest genomic builds and databases to better prioritize variants as potentially disease-causing for more complete molecular diagnosis in IRD patients.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":" ","pages":"1-7"},"PeriodicalIF":1.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}