Biallelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement
Biallelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement
Retinitis pigmentosa (RP) is an inherited retinal disease (IRD) characterized usually by progressive photoreceptor degeneration, leading to night blindness, peripheral visual field loss, and can progress to central vision impairment in some individuals. Despite advances in genomic diagnostics, many individuals with RP remain without a molecular diagnosis. We identified biallelic ultra-rare variants in FSD1L in six individuals with RP with or without neurological features from four unrelated families. FSD1L encodes a cytoplasmic protein, variants within which have not previously been associated with Mendelian disease. The gene is expressed in both human and mouse retina, enriched in cone and rod photoreceptors. Immunofluorescence and ultrastructure expansion microscopy show that FSD1L localizes along the photoreceptor microtubule axoneme, including the connecting cilium and outer segment, supporting a possible role in intracellular trafficking. A retina-enriched isoform of FSD1L includes an alternatively spliced exon (exon 10b), which we characterize as absent in minigene assays and affected individual-derived lymphocytes due to a deep intronic 26 nucleotide deletion. Together, these findings support the association between biallelic disruption of FSD1L and IRD.
FSD1L, cilia, genome sequencing, inherited retinal dystrophy, nanopore sequencing, retina-enriched isoform, retinal transcriptomics, retinitis pigmentosa, single-cell transcriptome, splice variant
616-626
Lin, Siying
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Lin, Siying
6b81f623-a082-40d6-b5ba-9ee21b5c1b69
Cancellieri, Francesca
1568111b-026a-4ab2-8840-95d679abb900
Cao, Yexuan
05b66c3b-b55e-4e2a-9c69-644321c96dd2
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Lin, Siying
a5f9720b-f9ef-46e5-90fc-c91d20438d3c
Lin, Siying
6b81f623-a082-40d6-b5ba-9ee21b5c1b69
Cancellieri, Francesca
1568111b-026a-4ab2-8840-95d679abb900
Cao, Yexuan
05b66c3b-b55e-4e2a-9c69-644321c96dd2
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Lin, Siying, Lin, Siying, Cancellieri, Francesca and Cao, Yexuan
,
et al.
(2026)
Biallelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement.
The American Journal of Human Genetics, 113 (3), .
(doi:10.1016/j.ajhg.2026.01.015).
Abstract
Retinitis pigmentosa (RP) is an inherited retinal disease (IRD) characterized usually by progressive photoreceptor degeneration, leading to night blindness, peripheral visual field loss, and can progress to central vision impairment in some individuals. Despite advances in genomic diagnostics, many individuals with RP remain without a molecular diagnosis. We identified biallelic ultra-rare variants in FSD1L in six individuals with RP with or without neurological features from four unrelated families. FSD1L encodes a cytoplasmic protein, variants within which have not previously been associated with Mendelian disease. The gene is expressed in both human and mouse retina, enriched in cone and rod photoreceptors. Immunofluorescence and ultrastructure expansion microscopy show that FSD1L localizes along the photoreceptor microtubule axoneme, including the connecting cilium and outer segment, supporting a possible role in intracellular trafficking. A retina-enriched isoform of FSD1L includes an alternatively spliced exon (exon 10b), which we characterize as absent in minigene assays and affected individual-derived lymphocytes due to a deep intronic 26 nucleotide deletion. Together, these findings support the association between biallelic disruption of FSD1L and IRD.
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PIIS0002929726000376
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Accepted/In Press date: 22 January 2026
e-pub ahead of print date: 19 February 2026
Keywords:
FSD1L, cilia, genome sequencing, inherited retinal dystrophy, nanopore sequencing, retina-enriched isoform, retinal transcriptomics, retinitis pigmentosa, single-cell transcriptome, splice variant
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Local EPrints ID: 510110
URI: http://eprints.soton.ac.uk/id/eprint/510110
ISSN: 0002-9297
PURE UUID: f4a80c6e-30d4-4d05-8d4b-4b77c9de7d50
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Date deposited: 17 Mar 2026 18:04
Last modified: 21 Mar 2026 02:46
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Author:
Siying Lin
Author:
Siying Lin
Author:
Francesca Cancellieri
Author:
Yexuan Cao
Corporate Author: et al.
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