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nilswagner.bsky.social

@nilswagner.bsky.social

nilswagner.bsky.social @nilswagner.bsky.social · 26/01/2026

Thanks to Aleks Neverov @paleontologm.bsky.social, all colleagues in the Gagneur lab @gagneurlab.bsky.social who contributed to this study, and to our collaborators Alexandra Martin-Geary and Nicky Whiffin @nickywhiffin.bsky.social.

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nilswagner.bsky.social @nilswagner.bsky.social · 26/01/2026

Genome-wide SNV scores (for AbSplice and Pangolin) are publicly available: AbSplice (GTEx tissues): doi.org/10.5281/zeno... AbSplice (Development): doi.org/10.5281/zeno... Pangolin: doi.org/10.5281/zeno... Score your own variants (including indels) here: absplice.cmm.cit.tum.de

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nilswagner.bsky.social @nilswagner.bsky.social · 26/01/2026

Beyond the developmental predictions, we improved the model's precision and robustness with: 1) improved splicing outlier ground truth, 2) richer set of predictive features from SpliceAI/Pangolin, 3) replacing binary splice site usage with continuous usage features.

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nilswagner.bsky.social @nilswagner.bsky.social · 26/01/2026

We predicted thousands of variants with a developmental impact genome-wide. In Genomics England, we identified a new candidate in FGFR1 for an individual with Kallmann syndrome. The variant’s effect is predicted to occur solely in an early developmental window that aligns with the disease mechanism.

Left: Acceptor-site creating variant (chr8:38428099:C>T, NM_023110.3:c.449-6G>A) in the AG exclusion zone of exon 6 of the FGFR1 gene that was identified in an individual within the NGRL recruited with hypertrophic hypogonadism. Variants that result in a loss of function in FGFR1 have been found to lead to the disease phenotype (Kallmann syndrome). The variant affects a weak splice site identified during embryogenesis (Develop. SpliceMaps, lower track) but not in the GENCODE annotation, which would result in a frameshift. Right: AbSplice predictions of the variant on the weak splice site. The effect is predicted to be strong only in the weeks 4-6 post conception.

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nilswagner.bsky.social @nilswagner.bsky.social · 26/01/2026

Within the rare-disease cohort Solve-RD, high-impact brain-specific predictions are significantly enriched in individuals affected by neurodevelopmental disorders (NDD) in NDD-linked genes. The predicted developmental timing of the splicing disruption correlates with the clinical age of onset.

Left: Enrichment of high impact variants (SpliceAI: 0.8, Pangolin: 0.8, AbSplice1: 0.2, AbSplice2: 0.2) in affected individuals diagnosed with neurological and neurodevelopmental disorders within the Solve-RD cohort. The odds ratios are computed across neurodevelopmental disorder disease genes. Note that AbSplice predictions for brain and cerebellum show the largest enrichments.
Right: Enrichment of purely developmental (i.e. variant affecting developmental stage and not adult stage), developmental (i.e. variant affecting developmental stage), adult (i.e. variant affecting adult stage) and purely adult (i.e. variant affecting adult stage and not developmental stage) variants in individuals within Solve-RD affected with neurological or neurodevelopmental disorders. Brain-specific scores from AbSplice are used. Odds ratios were computed for the different variant classes and individuals with early (from embryogenesis to toddler) and adult (above 40 years) age of onset for all genes (top) and neurodevelopmental disorder (NDD) genes (bottom). Note that the predicted developmental timing correlates with the clinical age of onset.

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nilswagner.bsky.social @nilswagner.bsky.social · 26/01/2026

Our aberrant splicing prediction model AbSplice originally used adult data, but splicing is developmentally dynamic. We extended the framework to capture a class of variants impacting exclusively early stages - these have previously stayed off our radar.

Variants (red star) in the vicinity of developmentally regulated alternative splice sites exhibit changing effects over the course of organ development. These dynamic changes are captured by developmental SpliceMaps and reflected in AbSplice predictions.

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nilswagner.bsky.social @nilswagner.bsky.social · 26/01/2026

How many high-impact developmental variants are we missing by relying only on adult splicing annotations? We address this in our preprint “Aberrant splicing prediction during human organ development”: www.biorxiv.org/content/10.1...

biorxiv.org

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