Clinical Characterization of 66 Patients With Congenital Retinal Disease Due to the Deep-Intronic c.2991+1655A&gt;G Mutation in<i>CEP290</i>

Valkenburg, Dyon; Cauwenbergh, Caroline Van; Lorenz, Birgit; Genderen, Mies M. van; Bertelsen, Mette; Pott, Jan Willem R.; Coppieters, Frauke; Zaeytijd, Julie De; Thiadens, Alberta A H J; Klaver, Caroline C W; Kroes, Hester Y.; Schooneveld, Mary J. van; Preising, Markus N.; Hoyng, Carel B.; Leroy, Bart P.; Born, L. Ingeborgh van den; Collin, Rob W.J.

doi:10.1167/iovs.18-24817

Cited by 24 publications

(22 citation statements)

References 33 publications

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“…Strong correlative evidence of a relationship between acuity and light sensitivity existed in our cohort. CEP290 - and NPHP5 -LCA patients in this study had a spectrum of visual acuity results from 20/50 to NLP, consistent with previous reports 61–64. Light sensitivity as measured with dark-adapted red (cone-mediated) FST measurements showed a relation with visual acuity – the better the visual acuity, the higher the FST sensitivities.…”

Section: Discussionsupporting

confidence: 90%

Treatment Potential for Macular Cone Vision in Leber Congenital Amaurosis Due toCEP290orNPHP5Mutations: Predictions From Artificial Intelligence

Sumaroka

Garafalo

Semenov

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To use supervised machine learning to predict visual function from retinal structure in retinitis pigmentosa (RP) and apply these estimates to CEP290-and NPHP5-associated Leber congenital amaurosis (LCA) to determine the potential for functional improvement. METHODS. Patients with RP (n ¼ 20) and LCA due to CEP290 (n ¼ 12) or NPHP5 (n ¼ 6) mutations were studied. A patient with CEP290 mutations but mild retinal degeneration was included. RP patients had cone-mediated macular function. A machine learning technique was used to associate perimetric sensitivities to local structure in RP patients. Models trained on RP data were applied to predict visual function in LCA. RESULTS. The RP and LCA patients had comparable retinal structure. RP patients had peak sensitivity at the fovea surrounded by decreasing sensitivity. Machine learning could successfully predict perimetry results from segmented or unsegmented optical coherence tomography (OCT) input. Application of machine learning predictions to LCA within the residual macular island of photoreceptor structure showed differences between predicted and measured sensitivities defining treatment potential. In patients with retained vision, the treatment potential was 4.6 6 2.9 dB at the fovea but 16.4 6 4.4 dB at the parafovea. In patients with limited or no vision, the treatment potential was 17.6 6 9.4 dB. CONCLUSIONS. Cone vision improvement potential in LCA due to CEP290 or NPHP5 mutations is predictable from retinal structure using a machine learning approach. This should allow individual prediction of the maximal efficacy in clinical trials and guide decisions about dosing. Similar strategies can be used in other retinal degenerations to estimate the extent and location of treatment potential.

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Section: Discussionsupporting

confidence: 90%

Treatment Potential for Macular Cone Vision in Leber Congenital Amaurosis Due toCEP290orNPHP5Mutations: Predictions From Artificial Intelligence

Sumaroka

Garafalo

Semenov

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Previous studies have consistently established the association of a deep intronic c.2991 + 1655A > G variant in the CEP290 gene with LCA, occurring in more than half of CEP290-associated cases [39,40]. This common variant correlates with the severe congenital retinal phenotype of LCA, resulting in legal blindness at a young age [41]. Therefore, when WES identifies one variant and a second variant is expected within the gene, Sanger sequencing of the suspected intronic region(s) may be more economical.…”

Section: Discussionmentioning

confidence: 89%

Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results

Cho

Carvalho

Tanaka

et al. 2020

Orphanet J Rare Dis

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Background: Whole exome sequencing (WES) allows for an unbiased search of the genetic cause of a disease. Employing it as a first-tier genetic testing can be favored due to the associated lower incremental cost per diagnosis compared to when using it later in the diagnostic pathway. However, there are technical limitations of WES that can lead to inaccurate negative variant callings. Our study presents these limitations through a re-evaluation of negative WES results using subsequent tests primarily driven by fundoscopic findings. These tests included targeted gene testing, inherited retinal gene panels, whole genome sequencing (WGS), and array comparative genomic hybridization. Results: Subsequent genetic testing guided by fundoscopy findings identified the following variant types causing retinitis pigmentosa that were not detected by WES: frameshift deletion and nonsense variants in the RPGR gene, 353bp Alu repeat insertions in the MAK gene, and large exonic deletion variants in the EYS and PRPF31 genes. Deep intronic variants in the ABCA4 gene causing Stargardt disease and the GUCY2D gene causing Leber congenital amaurosis were also identified. Conclusions: Negative WES analyses inconsistent with the phenotype should raise clinical suspicion. Subsequent genetic testing may detect genetic variants missed by WES and can make patients eligible for gene replacement therapy and upcoming clinical trials. When phenotypic findings support a genetic etiology, negative WES results should be followed by targeted gene sequencing, array based approach or whole genome sequencing.

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“…SD-OCT imaging showed a slightly reduced CRT, in agreement with previous reports. 22,25,26 Furthermore, an EZ band with a mean width of approximately 2.000 μm was detected in a high proportion of analyzed patients (83.3%). These findings revealed a better preserved EZ band compared to the cohort described by Feldhaus et al 26 with a mean width of about 1.000 μm.…”

Section: Discussionmentioning

confidence: 94%

Spectrum of Disease Severity in Nonsyndromic Patients With Mutations in the CEP290 Gene: A Multicentric Longitudinal Study

Testa

Sodi

Signorini³

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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The purpose of this study was to perform a detailed longitudinal phenotyping and genetic characterization of 32 Italian patients with a nonsyndromic retinal dystrophy and mutations in the CEP290 gene. METHODS.We reviewed the clinical history and examinations of 32 patients with a nonsyndromic retinal dystrophy due to mutations in the CEP290 gene, followed up (mean followup: 5.9 years) at 3 Italian centers. The clinical examinations included: best corrected visual acuity (BCVA), optical coherence tomography (OCT), and full-field electroretinogram (ERG). RESULTS.Patients (mean age = 19.0 ± 3.4 years) had a mean BCVA of 1.73 ± 0.20 logMAR. Longitudinal analysis of BCVA showed a nonsignificant decline. Central retinal thickness (CRT) declined significantly with age at an exponential rate of 1.0%/year (P = 0.001). At disease onset, most patients (19/32; 49.4%) had nystagmus. The absence of nystagmus was significantly associated with better BCVA and more preserved CRT (P < 0.05). ERG showed undetectable responses in most patients (64.0%), whereas reduced scotopic and photopic responses were observed in four patients (16.0%) who had no nystagmus. We identified 35 different variants, among which 12 were novel. Our genotype-phenotype correlation analysis shows a significantly worse BCVA in patients harboring a loss-offunction mutation and the deep-intronic variant c.2991+1655A>G. CONCLUSIONS.Our study highlights a mild phenotype of the disease, characterized by absence of nystagmus, good visual acuity, considerably preserved retinal morphology, and recordable ERG, confirming the wide spectrum of CEP290-related retinal dystrophies. Finally, in our cohort, the deep intronic variant c.2991+1655A>G was associated with a more severe phenotype.

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Clinical Characterization of 66 Patients With Congenital Retinal Disease Due to the Deep-Intronic c.2991+1655A>G Mutation inCEP290

Cited by 24 publications

References 33 publications

Treatment Potential for Macular Cone Vision in Leber Congenital Amaurosis Due toCEP290orNPHP5Mutations: Predictions From Artificial Intelligence

Treatment Potential for Macular Cone Vision in Leber Congenital Amaurosis Due toCEP290orNPHP5Mutations: Predictions From Artificial Intelligence

Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results

Spectrum of Disease Severity in Nonsyndromic Patients With Mutations in the CEP290 Gene: A Multicentric Longitudinal Study

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