Genome-Wide Analysis Reveals a Role of Non-coding 3'untranslated Region Variants Affecting Cleavage and Polyadenylation in Undiagnosed Rare Disorders

Yaroslav Kainov; C. Dias; T. Hubbard

doi:10.1101/2025.02.16.25322367

Genome-Wide Analysis Reveals a Role of Non-coding 3'untranslated Region Variants Affecting Cleavage and Polyadenylation in Undiagnosed Rare Disorders

Yaroslav Kainov^*, C. Dias, T. Hubbard

^*Corresponding author for this work

Medical & Molecular Genetics

Research output: Working paper/Preprint › Preprint

Abstract

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 alleles deleterious impact on gene expression.

Original language	Undefined/Unknown
Publisher	MedRxiv
DOIs	https://doi.org/10.1101/2025.02.16.25322367
Publication status	Published - 21 Feb 2025

Keywords

genetic and genomic medicine

Access to Document

10.1101/2025.02.16.25322367Licence: CC BY

Cite this

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abstract = "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 alleles deleterious impact on gene expression.",

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AB - 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 alleles deleterious impact on gene expression.

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