EMBO Molecular Medicine (Feb 2023)

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

  • 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

DOI
https://doi.org/10.15252/emmm.202216478
Journal volume & issue
Vol. 15, no. 2
pp. n/a – n/a

Abstract

Read online

Abstract 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.

Keywords