Publications by authors named "Chelsea Bender"

Article Synopsis
  • * The study identifies a new autosomal dominant syndrome combining eye malformations, spine issues, and kidney problems in six different families, linked to mutations in a specific orphan nuclear receptor gene.
  • * Genetic experiments demonstrated that these mutations disrupt normal development in zebrafish, highlighting the gene's crucial role in both eye and vertebra formation.
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Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe a novel autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities.

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Importance: Inherited retinal dystrophies (IRDs) present a challenge in clinical diagnostics due to their pronounced genetic heterogeneity. Despite advances in next-generation sequencing (NGS) technologies, a substantial portion of the genetic basis underlying IRDs remains elusive. Addressing this gap seems important for gaining insights into the genetic landscape of IRDs, which may help improve diagnosis and prognosis and develop targeted therapies in the future.

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Article Synopsis
  • * A systematic review identified 36 new pathogenic and 10 likely pathogenic variants through measuring esterase activity, creating a reliable method for classifying variants related to PNPLA6.
  • * The study revealed a significant link between NTE activity levels and the presence of specific symptoms like retinopathy and endocrinopathy, supporting the idea that PNPLA6 disorders are a spectrum of related phenotypes based on NTE genotype and activity, setting the stage for future therapies.
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Article Synopsis
  • Splice variants can cause diseases by changing the way mRNA is made, which can lead to problems in proteins.
  • Scientists can confirm these changes by looking at the mRNA sequences in tests.
  • A new method called qMini helped researchers find a type of splice variant that lowers the amount of mRNA without changing its sequence, pointing to a new way diseases might develop.
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Article Synopsis
  • Biallelic pathogenic variants in the NTE gene are linked to various disorders that cause issues like gait disturbance, visual impairment, and hormonal problems such as anterior hypopituitarism.
  • A clinical meta-analysis of new and previously reported patients identifies specific missense variants as significant contributors to disease pathogenesis, with a developed functional assay helping to classify variants of unknown significance.
  • Findings show a clear connection between reduced NTE activity and the occurrence of certain conditions (retinopathy and endocrinopathy), suggesting a continuous spectrum of disorders based on NTE functionality, which may guide future therapeutic strategies.
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Purpose: Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity. We have previously shown knockdown of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma.

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Choroideremia is an X-linked, blinding retinal degeneration with progressive loss of photoreceptors, retinal pigment epithelial (RPE) cells, and choriocapillaris. To study the extent to which these layers are disrupted in affected males and female carriers, we performed multimodal adaptive optics imaging to better visualize the in vivo pathogenesis of choroideremia in the living human eye. We demonstrate the presence of subclinical, widespread enlarged RPE cells present in all subjects imaged.

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Importance: Sorsby fundus dystrophy is a typically adult-onset maculopathy with high risk for choroidal neovascularization. Sorsby fundus dystrophy, inherited as an autosomal dominant fully penetrant trait, is associated with TIMP3 variants that cause protein aggregation in the extracellular matrix.

Objective: To evaluate the phenotype and underlying biochemical mechanism of disease-causing TIMP3 variants altering the N-terminal signal peptide in 2 families who have early-onset diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence.

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For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic variants exclusively cause X-linked retinoschisis (XLRS). While is constrained to variation, recurrent variants are frequently observed in unrelated probands.

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Importance: Asymmetric retinitis pigmentosa (RP) is a rare presentation of a normally symmetric condition. Histopathologic evidence should be examined to see if this asymmetry extends to the tissue and cellular levels.

Objective: To determine whether additional information can be obtained about asymmetric RP from studying clinical imaging and pathology correlates, including pathology samples from autopsied eyes.

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Article Synopsis
  • The eyeGENE® network conducted a retrospective review of genetic testing data for inherited eye conditions, enrolling 6,403 participants diagnosed with over 30 different conditions from clinics across the U.S. and Canada.
  • Blood samples and clinical data were collected to create a comprehensive database and registry, revealing that 62.1% of participants had pathogenic variants, primarily in genes like ABCA4, USH2A, and RPGR.
  • The findings from eyeGENE not only offer insight into genetic causes of eye diseases but also identify over a thousand participants potentially eligible for gene therapy clinical trials, making it a key resource for future research in inherited eye conditions.
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