Alternative splicing analysis in a Spanish ASD (Autism Spectrum Disorders) cohort: in silico prediction and...

Area of Science:

• Genetics and Genomics
• Neurodevelopmental Disorders
• Computational Biology

Background:

• Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions with heterogeneous genetic underpinnings.
• Alternative splicing (AS) is increasingly recognized as a contributor to ASD pathogenesis, yet its role in large-scale genomic studies remains underexplored.

Purpose of the Study:

• To computationally identify, predict, and validate splicing variants in a Spanish ASD cohort.
• To investigate the potential contribution of these splicing variants to ASD etiology and their tissue-specific impacts.

Main Methods:

• Utilized SpliceAI for high-confidence splicing variant identification in 360 Spanish ASD trios (threshold Δ ≥ 0.8).
• Performed in silico validation using SpliceVault with 335,663 RNA-sequencing datasets (GTEx v8, SRA) and orthogonal confirmation with ABSplice.
• Conducted gene validation and Gene Ontology (GO) analysis using complementary datasets from over 42,000 ASD cases.

Main Results:

• Identified potential contributions of splicing variants in genes including CACNA1I, CBLB, CLTB, DLGAP1, DVL3, KIAA0513, OFD1, PKD1, SLC13A3, and SCN2A.
• Revealed tissue-specific effects of splicing variants, particularly in adipose tissue, testis, and the brain.
• Splicing genes were predominantly associated with synaptic organization and transmission, contrasting with non-splicing ASD genes linked to chromatin remodeling.

Conclusions:

• This study advances the understanding of alternative splicing's role in ASD pathogenesis.
• Findings suggest specific tissues and molecular pathways, including synaptic function, are involved in ASD.
• Further in vitro validation and multi-omics integration are warranted to elucidate functional roles and regulatory interplay.