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DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration

DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration
DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration
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.

DYNC2H1, inherited retinal disease (IRD), intraflagellar transport (IFT), primary cilia, retinitis pigmentosa (RP)
1098-3600
2041-2051
Vig, Anjali
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Poulter, James A.
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Mollica, Antonio
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Paton, Tara
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Maynes, Jason T.
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Wheway, Gabrielle
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Arumugam, P.
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Baple, E. L.
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Bleda, M.
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Brittain, H.
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Caulfield, M. J.
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Chan, G. C.
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Craig, C.E.H.
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Daugherty, L. C.
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de Burca, A.
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Devereau, A.
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Elgar, G.
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Foulger, R. E.
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Furió-Tarí, P.
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Hackett, J. M.
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Halai, D.
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Hamblin, A.
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Henderson, S.
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Holman, J. E.
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Hubbard, T. J.P.
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Ibáñez, K.
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Jackson, R.
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Jones, L. J.
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Mason, J.
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McDonagh, E. M.
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Mueller, M.
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Scott, R. H.
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Smith, K. R.
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Thomas, E. R.A.
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Thompson, S.R.
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Walsh, E.
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Williams, E.
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Wood, S. M.
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et al.
Genomics England Research Consortium
Vig, Anjali
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Poulter, James A.
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Ottaviani, Daniele
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Tavares, Erika
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Toropova, Katerina
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Tracewska, Anna Maria
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Mollica, Antonio
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Kang, Jasmine
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Kehelwathugoda, Oshini
eaa7bdd1-1072-4b9b-b42a-1615232a4ed7
Paton, Tara
a5c40067-9a54-4bfe-ace6-41d4fbe3ccbf
Maynes, Jason T.
a78f7aac-d57d-4daf-8ba9-5e1dedfd6112
Wheway, Gabrielle
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Arno, Gavin
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Ambrose, J. C.
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Arumugam, P.
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Baple, E. L.
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Bleda, M.
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Boardman-Pretty, F.
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Boissiere, J. M.
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Boustred, C. R.
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Brittain, H.
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Caulfield, M. J.
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Chan, G. C.
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Craig, C.E.H.
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Daugherty, L. C.
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de Burca, A.
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Devereau, A.
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Elgar, G.
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Foulger, R. E.
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Fowler, T.
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Furió-Tarí, P.
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Hackett, J. M.
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Halai, D.
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Hamblin, A.
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Henderson, S.
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Holman, J. E.
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Hubbard, T. J.P.
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Ibáñez, K.
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Jackson, R.
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Jones, L. J.
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Mason, J.
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McDonagh, E. M.
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Mueller, M.
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Scott, R. H.
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Smith, K. R.
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Thomas, E. R.A.
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Thompson, S.R.
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Walsh, E.
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Williams, E.
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Wood, S. M.
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Vig, Anjali, Poulter, James A. and Ottaviani, Daniele , et al. and Genomics England Research Consortium (2020) DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration. Genetics in Medicine, 22 (12), 2041-2051. (doi:10.1038/s41436-020-0915-1).

Record type: Article

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.

This record has no associated files available for download.

More information

Accepted/In Press date: 16 July 2020
e-pub ahead of print date: 5 August 2020
Published date: 5 August 2020
Keywords: DYNC2H1, inherited retinal disease (IRD), intraflagellar transport (IFT), primary cilia, retinitis pigmentosa (RP)

Identifiers

Local EPrints ID: 444752
URI: http://eprints.soton.ac.uk/id/eprint/444752
DOI: doi:10.1038/s41436-020-0915-1
ISSN: 1098-3600
PURE UUID: 24e27ca7-5770-4be5-8e63-c0bdb9af230e
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783

Catalogue record

Date deposited: 03 Nov 2020 17:32
Last modified: 18 Mar 2024 03:49

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Contributors

Author: Anjali Vig
Author: James A. Poulter
Author: Daniele Ottaviani
Author: Erika Tavares
Author: Katerina Toropova
Author: Anna Maria Tracewska
Author: Antonio Mollica
Author: Jasmine Kang
Author: Oshini Kehelwathugoda
Author: Tara Paton
Author: Jason T. Maynes
Author: Gabrielle Wheway ORCID iD
Author: Gavin Arno
Author: J. C. Ambrose
Author: P. Arumugam
Author: E. L. Baple
Author: M. Bleda
Author: F. Boardman-Pretty
Author: J. M. Boissiere
Author: C. R. Boustred
Author: H. Brittain
Author: M. J. Caulfield
Author: G. C. Chan
Author: C.E.H. Craig
Author: L. C. Daugherty
Author: A. de Burca
Author: A. Devereau
Author: G. Elgar
Author: R. E. Foulger
Author: T. Fowler
Author: P. Furió-Tarí
Author: J. M. Hackett
Author: D. Halai
Author: A. Hamblin
Author: S. Henderson
Author: J. E. Holman
Author: T. J.P. Hubbard
Author: K. Ibáñez
Author: R. Jackson
Author: L. J. Jones
Author: J. Mason
Author: E. M. McDonagh
Author: M. Mueller
Author: R. H. Scott
Author: K. R. Smith
Author: E. R.A. Thomas
Author: S.R. Thompson
Author: E. Walsh
Author: E. Williams
Author: S. M. Wood
Corporate Author: et al.
Corporate Author: Genomics England Research Consortium

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