Bi-allelic 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 bi-allelic ultra-rare variants in fibronectin type II and Spry domain-containing protein 1-like (FSD1L) in six individuals with RP with or without neurological features from four unrelated families. FSD1L encodes a cytoplasmic protein, variants of which have not previously been associated with Mendelian disease. The gene is expressed in both human and mouse retinas that are 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 nt deletion. Together, these findings support the association between bi-allelic disruption of FSD1L and IRD.

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Publication Details

Journal
The American Journal of Human Genetics
Published
2026-02-19
DOI
https://doi.org/10.1016/j.ajhg.2026.01.015
Primary Topic
Retinal Development and Disorders
Type
article
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article

Bi-allelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement

Shyamanga Borooah, Debarshi Mustafi, Aleksander Tworak, Sandrine Wallerich et al.
The American Journal of Human Genetics
Retinal Development and Disorders
article

Bi-allelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement

Shyamanga Borooah, Debarshi Mustafi, Aleksander Tworak, Sandrine Wallerich, Ana Belén Iglesias-Romero, Roman Šmidák, Karolina Kamińska, Fabienne Perren, Francesca Cancellieri, O. Mahroo, Abigail R. Moye, Veronika Vaclavik, Rui Chen, Andrzej Poplawski, A. Jestin, Carlo Rivolta, Siying Lin, Gavin Arno, Simone Picelli, Mariana M. Ribeiro, Yexuan Cao, Jiaxiong Lu, Andrew R. Webster, Yumei Li, Meng Wang, Krzysztof Palczewski, Elena R. Schiff, Marc Folcher, Andrew J. Lotery
article en

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 bi-allelic ultra-rare variants in fibronectin type II and Spry domain-containing protein 1-like (FSD1L) in six individuals with RP with or without neurological features from four unrelated families. FSD1L encodes a cytoplasmic protein, variants of which have not previously been associated with Mendelian disease. The gene is expressed in both human and mouse retinas that are 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 nt deletion. Together, these findings support the association between bi-allelic disruption of FSD1L and IRD.

The American Journal of Human GeneticsVol. 113(3)
Moorfields Eye Hospital NHS Foundation Trust (GB), University of Fribourg (CH), University of California, Irvine (US), Southampton Hospital (US), Southampton General Hospital (GB), National Institute for Health and Care Research (GB), University of California San Diego (US), St Mary's Hospital (GB), Seattle Children's Hospital (US), Fondation Asile des Aveugles (CH), Greenwood Genetic Center (US), Institute of Molecular and Clinical Ophthalmology Basel (CH), University of Southampton (GB), University College London (GB), University of Lausanne (CH)
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Retinal Development and Disorders
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