B-S.B.53: MCVAE-based multi-omic anomaly detection in Fragile X Syndrome
Fragile X Syndrome (FXS) is a
neurodevelopmental disorder caused by mutations
in the FMR1 gene, resulting in the loss of FMRP,
an RNA-binding protein regulating translation
of hundreds of mRNAs. The Fmr1 knock-out
mouse models this deficiency and is used
to study molecular perturbations in the FXS
brain. Omics analysis shows that FMRP loss
disrupts coordination between transcriptomic and
translatomic layers. But limited sample availability
and dataset heterogeneity hinder detection of
subtle, coordinated multi-omic dysregulations.
To address this, we trained a Multi-Channel
Variational Autoencoder (MCVAE) on wild-type
samples to learn a shared latent representation
of transcriptomic and translatomic modalities
via cross-modal reconstruction. Testing MCVAE
on Fmr1-knock-out samples revealed deviations
from wild-type as anomalies, uncovering known
and novel perturbations. Compared to alternative
methods, MCVAE shows stronger enrichment
for FMRP mRNA targets and improved genotype
discriminative power in post-hoc tests. Translatomic
anomalies exhibited coordinated relationships
with transcriptomic anomalies, as supported by
publicly available databases exploration. Moreover,
these anomalies mapped to validated FMRP
regulators and neurodevelopmental pathways,
establishing MCVAE as a framework to uncover
coordinated molecular perturbations underlying
the FXS pathophysiology and guide biomarker and
therapeutic target identification.
Co-authors: None
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