Vig, A. and Poulter, J.A. and Ottaviani, D. and Tavares, E. and Toropova, K. and Tracewska, A.M. and Mollica, A. and Kang, J. and Kehelwathugoda, O. and Paton, T. and Maynes, J.T. and Wheway, G. and Arno, G. and Genomics England Research, C. and Khan, K.N. and McKibbin, M. and Toomes, C. and Ali, M. and Di Scipio, M. and Li, S. and Ellingford, J. and Black, G. and Webster, A. and Rydzanicz, M. and Stawiński, P. and Płoski, R. and Vincent, A. and Cheetham, M.E. and Inglehearn, C.F. and Roberts, Anthony J. and Heon, E. (2020) DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration. Genetics in Medicine 22 (12), pp. 2041-2051. ISSN 1530-0366.
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Abstract
Purpose: Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). Methods: Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). Results: Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2–4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). Conclusion: The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Anthony Roberts |
| Date Deposited: | 12 Aug 2020 08:22 |
| Last Modified: | 02 Aug 2023 18:01 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/32848 |
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