Researcher:
Sarıbaş, Burak

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Master Student

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Burak

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Sarıbaş

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Sarıbaş, Burak

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20231

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    A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing
    (John Wiley and Sons Inc, 2023) Bressin, Annkatrin; Shboul, Mohammad; Moreno Traspas, Ricardo; Chia, Poh Hui; Bonnard, Carine; Szenker-Ravi, Emmanuelle; Beillard, Emmanuel; Hojati, Zohreh; Drutman, Scott; Freier, Susanne; El-Khateeb, Mohammad; Fathallah, Rajaa; Casanova, Jean-Laurent; Soror, Wesam; Arafat, Alaa; Mayer, Andreas; Altunoğlu, Umut; Reversade, Bruno; Nabavizadeh, Nasrinsadat; Sarıbaş, Burak; Faculty Member; Faculty Member; Researcher; Researcher; Master Student; School of Medicine; School of Medicine; School of Medicine; N/A; Graduate School of Health Sciences; 126174; 274182; N/A; N/A; N/A
    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.