@nilswagner.bsky.social

@nilswagner.bsky.social

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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.
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.
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.