298: Bi-allelic FSD1L variants in retinitis pigmentosa implicate photoreceptor axoneme

Lin S et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.015 - Bi-allelic FSD1L variants cause retinitis pigmentosa; FSD1L localizes to the photoreceptor axoneme and a deep intronic deletion abolishes retina-enriched exon 10b inclusion. Key terms: FSD1L, retinitis pigmentosa, photoreceptor axoneme, exon 10b, minigene assay.

Study Highlights:
In human and mouse retinal tissues and six affected individuals from four families, exome/genome sequencing identified bi-allelic ultra-rare FSD1L variants associated with retinitis pigmentosa. Single-cell RNA-seq, immunofluorescence, and ultrastructure expansion microscopy show FSD1L is enriched in cones and rods and localizes along the photoreceptor microtubule axoneme including the connecting cilium and outer segment. Functional assays including ARPE-19 minigene splicing and long-read nanopore sequencing of patient lymphocytes demonstrate that a deep intronic 26-nt deletion abolishes inclusion of a retina-enriched exon (exon 10b). Together these data link isoform-specific mis-splicing and axonemal localization to a plausible disruption of intracellular trafficking leading to photoreceptor degeneration.

Conclusion:
Bi-allelic disruption of FSD1L is associated with retinitis pigmentosa, and retina-enriched exon 10b mis-splicing provides a plausible mechanism for isolated retinal disease.

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

First author:
Lin S

Journal:
The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2026.01.015

DOI:
10.1016/j.ajhg.2026.01.015

Reference:
Lin S., Cancellieri F., Cao Y., et al. Bi-allelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement. The American Journal of Human Genetics 113, 1–11 (2026). https://doi.org/10.1016/j.ajhg.2026.01.015

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive scientific content in the transcript: discovery of bi-allelic FSD1L variants in RP families; retina-enriched isoform with exon 10b; deep intronic deletion disrupting exon 10b; minigene splicing assays; FSD1L localization to photoreceptor axoneme/connecting cilium/outer segment; expression pattern in
- transcript topics: RP and inherited retinal disease overview; FSD1L as RP gene candidate; Retina-enriched isoform and exon 10b; Deep intronic deletion c.1025+624_1025+649del and exon 10b skipping; Minigene splicing assays in ARPE-19 cells; FSD1L localization to photoreceptor axoneme via U-ExM

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
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- article_title
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Factual Items Audited:
- Bi-allelic ultra-rare FSD1L variants identified in six indiv...

Chapters

• (00:00:11) - The missing heritability of inherited retinal diseases
• (00:03:00) - Globally, retinal disease 1, Introduction
• (00:04:14) - The genetic cause of blindness
• (00:08:28) - The secret to retinitis pigmentosa
• (00:13:54) - Deep Dive into the dark corners of the genome
• (00:17:21) - Follow the Light Along the Axle