Optical Coherence Tomography Feature of Retinoschisis in <i>CRB1</i>-Associated Maculopathy

Bellingrath, Julia-Sophia; Birtel, Johannes; Yusuf, Imran H.; MacLaren, Robert E.; Charbel Issa, Peter

doi:10.1001/jamaophthalmol.2023.5886

Cited by 1 publication

(1 citation statement)

References 6 publications

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“…CRB1-associated IRDs do Over 150 disease-associated variants leading to a variety of retinal degenerations, most commonly to Leber congenital amaurosis and early-onset rod-cone dystrophy (52%) but also to retinitis pigmentosa (25%), have been described in the CRB1 gene by the Human Gene Mutation Database (http://www.hgmd.org, last accessed on 7 January 2024) [9]. Hypomorphic alleles, often in-frame deletions, have been shown to cause macular degeneration (MD, 23%), a milder phenotype [10][11][12]. The typical morphological features of CRB1-associated inherited retinal degenerations (IRDs) can include an abnormally laminated and thickened retina [13], peripheral exudative retinal telangiectasia (Coats-like vasculopathy) [14], preservation of the para-arteriolar retinal pigment epithelium [15], foveal retinoschisis [16,17], hyperopia [18], nanophthalmos [19], nummular pigmentation [20], and optic disc drusen [21].…”

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confidence: 99%

In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A

Shamsnajafabadi,

Kaukonen,

Bellingrath

et al. 2024

Genes

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Pathogenic variants in the Crumbs homolog 1 (CRB1) gene lead to severe, childhood-onset retinal degeneration leading to blindness in early adulthood. There are no approved therapies, and traditional adeno-associated viral vector-based gene therapy approaches are challenged by the existence of multiple CRB1 isoforms. Here, we describe three CRB1 variants, including a novel, previously unreported variant that led to retinal degeneration. We offer a CRISPR-Cas-mediated DNA base editing strategy as a potential future therapeutic approach. This study is a retrospective case series. Clinical and genetic assessments were performed, including deep phenotyping by retinal imaging. In silico analyses were used to predict the pathogenicity of the novel variant and to determine whether the variants are amenable to DNA base editing strategies. Case 1 was a 24-year-old male with cone–rod dystrophy and retinal thickening typical of CRB1 retinopathy. He had a relatively preserved central outer retinal structure and a best corrected visual acuity (BCVA) of 60 ETDRS letters in both eyes. Genetic testing revealed compound heterozygous variants in exon 9: c.2843G>A, p.(Cys948Tyr) and a novel variant, c.2833G>A, p.(Gly945Arg), which was predicted to likely be pathogenic by an in silico analysis. Cases 2 and 3 were two brothers, aged 20 and 24, who presented with severe cone–rod dystrophy and a significant disruption of the outer nuclear layers. The BCVA was reduced to hand movements in both eyes in Case 2 and to 42 ETDRS letters in both eyes in Case 3. Case 2 was also affected with marked cystoid macular lesions, which are common in CRB1 retinopathy, but responded well to treatment with oral acetazolamide. Genetic testing revealed two c.2234C>T, p.(Thr745Met) variants in both brothers. As G-to-A and C-to-T variants, all three variants are amenable to adenine base editors (ABEs) targeting the forward strand in the Case 1 variants and the reverse strand in Cases 2 and 3. Available PAM sites were detected for KKH-nSaCas9-ABE8e for the c.2843G>A variant, nSaCas9-ABE8e and KKH-nSaCas9-ABE8e for the c.2833G>A variant, and nSpCas9-ABE8e for the c.2234C>T variant. In this case series, we report three pathogenic CRB1 variants, including a novel c.2833G>A variant associated with early-onset cone–rod dystrophy. We highlight the severity and rapid progression of the disease and offer ABEs as a potential future therapeutic approach for this devastating blinding condition.

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Section: Introductionmentioning

confidence: 99%

In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A

Shamsnajafabadi,

Kaukonen,

Bellingrath

et al. 2024

Genes

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Optical Coherence Tomography Feature of Retinoschisis in CRB1-Associated Maculopathy

Abstract: This case report describes 2 individuals with hyperreflective columns in the outer nuclear layer observed on optical coherence tomography and possible implications for CRB1-associated maculopathy.

Cited by 1 publication

References 6 publications

In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A

In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A

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