AlphaGenome identifies a deep intronic variant in a family with PLA2G6-associated neurodegeneration: Closing the diagnostic gap in rare genetic diseases

The article describes a case of two siblings with PLA2G6-associated neurodegeneration (PLAN) presenting with early-onset parkinsonism, neuropsychiatric features, and autonomic dysfunction. Despite previous genetic testing including clinical exome sequencing and long-read sequencing, only one heterozygous variant was identified. Using the AI model AlphaGenome, 91 non-coding variants in the PLA2G6 gene region were analyzed. The model identified a deep intronic variant (c.2034+355G>A) that creates a cryptic splice acceptor site and could lead to inclusion of a 160-bp cryptic exon. Tissue-specific predictions indicated that aberrant splicing would be detectable in blood, confirmed by RNA-seq analysis. This analysis completed the diagnosis nearly two decades after symptom onset and demonstrates the utility of sequence-to-function models in diagnosing rare genetic diseases.