Cleavage and polyadenylation of mRNAs is essential for transcription termination and gene expression, yet variants disrupting conserved sequences essential to this process are often overlooked as putative causal variants in individuals with rare Mendelian disorders. Using deep learning models, we identified enrichment of ultrarare alleles predicted to disrupt polyadenylation in a large cohort of undiagnosed probands with rare disease disorders from the Genomics England 100kGP dataset. These alleles are predominantly located in the 3′ UTRs of genes where protein-coding variants have previously been identified as causal in rare diseases. Experimental validation of a putative causal variant predicted to disrupt polyadenylation of SLC16A2 in a proband with intellectual disability, confirmed the allele′s deleterious impact on gene expression.

The authors have declared no competing interest.

This study has been possible thanks to a grant from Guy′s & St Thomas′ Charity grant STR111001

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This work used data from the 100 000 Genomes Project (IRAS ID 166046; East of England - Cambridge South Research Ethics Committee reference 14/EE/1112), which obtained written informed consent from all participants (or from their parent/legal guardian). All investigations were conducted in accordance with the tenets of the Declaration of Helsinki.

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