A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing.

Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non-coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA-seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA-seq, we delineated a deep intronic TAPT1 mutation (c.1237-52 G>A) that segregated with the disease. Using SI-NET-seq, we document that TAPT1's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre-mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein-null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease-relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non-coding variants, as well as in illuminating the molecular mechanisms of human diseases. © 2023 The Authors. Published under the terms of the CC BY 4.0 license.

Citation

Nasrinsadat Nabavizadeh, Annkatrin Bressin, Mohammad Shboul, Ricardo Moreno Traspas, Poh Hui Chia, Carine Bonnard, Emmanuelle Szenker-Ravi, Burak Sarıbaş, Emmanuel Beillard, Umut Altunoglu, Zohreh Hojati, Scott Drutman, Susanne Freier, Mohammad El-Khateeb, Rajaa Fathallah, Jean-Laurent Casanova, Wesam Soror, Alaa Arafat, Nathalie Escande-Beillard, Andreas Mayer, Bruno Reversade. A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing. EMBO molecular medicine. 2023 Feb 08;15(2):e16478

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PMID: 36652330

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