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A novel pathogenic CRB1 variant presenting as Leber Congenital Amaurosis 8 and evaluation of gene editing feasibility

  • Clinical Case Report
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Abstract

Introduction

Leber Congenital Amaurosis (LCA) is an inherited retinal disease that presents in infancy with severely decreased vision, nystagmus, and extinguished electroretinography findings. LCA8 is linked to variants in the Crumbs homolog 1 (CRB1) gene.

Case Description

We report a novel CRB1 variant in a 14-year-old male presenting with nystagmus, worsening vision, and inability to fixate on toys in his infancy. Color fundus photography revealed nummular pigments in the macula and periphery. Imaging studies revealed thickened retina on standard domain optical coherence tomography and widespread atrophy of the retinal pigment epithelium on autofluorescence. Full-field electroretinography revealed extinguished scotopic and significantly reduced photopic responses. Genetic testing demonstrated a novel homozygous variant, c.3057 T > A; p.(Tyr1019Ter), in the CRB1 gene. This variant is not currently amenable to base editing, however, in silico analysis revealed several potential prime editing strategies for correction.

Conclusion

This case presentation is consistent with LCA8, suggesting pathogenicity of this novel variant and expanding our knowledge of disease-causing CRB1 variants.

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Acknowledgements

We thank the Jonas Children’s Vision Care (JCVC) team and Quinn Lab members for their support and comradery.

Funding

B.L.D.C. is a recipient of the Capes PhD scholarship. S.H.T. and Jonas Children's Vision Care is supported by the National Institute of Health 5P30CA013696, U01 EY030580, U54OD020351, R24EY028758, R24EY027285, 5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437, the Schneeweiss Stem Cell Fund, New York State [SDHDOH01-C32590GG-3450000], the Foundation Fighting Blindness New York Regional Research Center Grant [TA-NMT-0116–0692-COLU], Nancy & Kobi Karp, the Crowley Family Funds, The Rosenbaum Family Foundation, Alcon Research Institute, the Gebroe Family Foundation, the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA. P.M.J.Q. is supported by the Curing Retinal Blindness Foundation (CRBF), a New York Stem Cell Foundation (NYSCF)—Druckenmiller Fellowship, and by the National Eye Institute, National Institutes of Health, through Grant Number R01EY034952.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA

    Mohamed M. Sylla, Masha Kolesinkova, Irene H. Maumenee, Stephen H. Tsang & Peter M. J. Quinn

  2. Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, NY, USA

    Mohamed M. Sylla, Masha Kolesinkova, Irene H. Maumenee & Stephen H. Tsang

  3. State University of New York at Downstate Health Sciences University, Brooklyn, NY, USA

    Mohamed M. Sylla & Masha Kolesinkova

  4. Department of Biomedical Engineering, Columbia University, New York, NY, USA

    Bruna Lopes da Costa & Stephen H. Tsang

  5. Columbia Stem Cell Initiative, Columbia University, New York, NY, USA

    Stephen H. Tsang

  6. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    Stephen H. Tsang

  7. Department of Ophthalmology, Columbia University Irving Medical Center, Hammer Health Sciences Building, 701 West 168th Street, New York, NY, 10032, USA

    Peter M. J. Quinn

Authors
  1. Mohamed M. Sylla
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  2. Masha Kolesinkova
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  3. Bruna Lopes da Costa
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  4. Irene H. Maumenee
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  5. Stephen H. Tsang
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  6. Peter M. J. Quinn
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Corresponding author

Correspondence to Peter M. J. Quinn.

Ethics declarations

Conflict of interest

S.H.T receives financial support from Abeona Therapeutics, Inc and Emendo and is on the scientific and clinical advisory board for Nanoscope Therapeutics. Columbia University has filed patent applications related to CRB1 for which B.L.D.C, S.H.T, and P.M.J.Q are listed as inventors. M.S., M.K. and I.H.M. have no conflicting interests.

Ethical approval

The study was conducted under the Columbia University Institutional Review Board-approved protocol IRB AAAF1849. All procedures were performed in compliance with the tenets of the Declaration of Helsinki. Informed consent was waived due to the retrospective nature of the study and the minimal risk conferred to patients as per the Columbia University Institutional Review Board-approved protocol AAAR8743.

Statement of human rights

The study was conducted under the Columbia University Institutional Review Board-approved protocol IRB AAAF1849. All procedures were performed in compliance with the tenets of the Declaration of Helsinki.

Statement on the welfare of animals

No animals were used in this study.

Informed consent

Informed consent was waived due to the retrospective nature of the study and the minimal risk conferred to patients as per the Columbia University Institutional Review Board-approved protocol AAAR8743.

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Sylla, M.M., Kolesinkova, M., da Costa, B.L. et al. A novel pathogenic CRB1 variant presenting as Leber Congenital Amaurosis 8 and evaluation of gene editing feasibility. Doc Ophthalmol 147, 217–224 (2023). https://doi.org/10.1007/s10633-023-09951-w

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  • DOI: https://doi.org/10.1007/s10633-023-09951-w

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