Novel partial loss-of-function variants in the tyrosyl-tRNA synthetase 1 (YARS1) gene involved in multisystem disease

• DOI: 10.1016/j.ejmg.2021.104294
• Publication Date: 2021-08-03T01:06:33Z
• Authors: Clothilde Estève; Céline Roman; Cécile DeLeusse; Melissa Baravalle; Karine Bertaux; Frédéric Blanc; Patrice Bourgeois; Violaine Bresson; Aline Cano; Marie-Edith Coste; Clémence Delteil; Caroline Lacoste; Marie Loosveld; André Maues De Paula; Anne-Sophie Monnier; Véronique Secq; Nicolas Levy; Catherine Badens; Alexandre Fabre
• Keywords: Amino Acyl-tRNA Synthetases; Aminoacylation; Failure to Thrive; Loss function

Cytoplasmic aminoacyl-tRNA synthetases (ARSs) are emerging as a cause of numerous rare inherited diseases. Recently, biallelic variants in tyrosyl-tRNA synthetase 1 (YARS1) have been described in ten patients of three families with multi-systemic disease (failure to thrive, developmental delay, liver dysfunction, and lung cysts). Here, we report an additional subject with overlapping clinical findings, heterozygous for two novel variants in tyrosyl-tRNA synthetase 1 (NM_003680.3(YARS1):c.176T>C; p.(Ile59Thr) and NM_003680.3(YARS1):c.237C>G; p.(Tyr79*) identified by whole exome sequencing. The p.Ile59Thr variant is located in the highly conserved aminoacylation domain of the protein. Compared to subjects previously described, this patient presents a much more severe condition. Our findings support implication of two novel YARS1 variants in these disorders. Furthermore, we provide evidence for a reduced protein abundance in cells of the patient, in favor of a partial loss-of-function mechanism.