Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function

article Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function published yes Sheng-Jia Lin author Barbara Vona author Hillary M. Porter author Mahmoud Izadi author Kevin Huang author 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe30000-0002-2512-7812 Yves Lacassie author Jill A. Rosenfeld author Saadullah Khan author Cassidy Petree author Tayyiba A. Ali author Nazif Muhammad author Sher A. Khan author Noor Muhammad author Pengfei Liu author Marie-Louise Haymon author Franz Rueschendorf author Il-Keun Kong author Linda Schnapp author Natasha Shur author Lynn Chorich author Lawrence Layman author Thomas Haaf author Ehsan Pourkarimi author Hyung-Goo Kim author Gaurav K. Varshney author Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars-1 in a Caenorhabditis elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients. https://research-explorer.ista.ac.at/download/14356/14370/2022_HumanMutation_Lin.pdf application/pdfno Wiley2022 eng autosomal recessivebiallelic variantsCeleganstranslation initiation sitestryptophanyl-tRNA synthetase 1 (WARS1)WHEP domainzebrafish Human Mutation 1059-779410.1002/humu.24435 43101472-1489 yes Lin S-J, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon M-L, Rueschendorf F, Kong I-K, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, Pourkarimi E, Kim H-G, Varshney GK. 2022. Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function. Human Mutation. 43(10), 1472–1489. Lin, S.-J., Vona, B., Porter, H. M., Izadi, M., Huang, K., Lacassie, Y., … Varshney, G. K. (2022). Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function. Human Mutation. Wiley. <a href="https://doi.org/10.1002/humu.24435">https://doi.org/10.1002/humu.24435</a> Lin, Sheng-Jia, Barbara Vona, Hillary M. Porter, Mahmoud Izadi, Kevin Huang, Yves Lacassie, Jill A. Rosenfeld, et al. “Biallelic Variants in WARS1 Cause a Highly Variable Neurodevelopmental Syndrome and Implicate a Critical Exon for Normal Auditory Function.” Human Mutation. Wiley, 2022. <a href="https://doi.org/10.1002/humu.24435">https://doi.org/10.1002/humu.24435</a>. Lin, Sheng-Jia, et al. “Biallelic Variants in WARS1 Cause a Highly Variable Neurodevelopmental Syndrome and Implicate a Critical Exon for Normal Auditory Function.” Human Mutation, vol. 43, no. 10, Wiley, 2022, pp. 1472–89, doi:<a href="https://doi.org/10.1002/humu.24435">10.1002/humu.24435</a>. S.-J. Lin, B. Vona, H.M. Porter, M. Izadi, K. Huang, Y. Lacassie, J.A. Rosenfeld, S. Khan, C. Petree, T.A. Ali, N. Muhammad, S.A. Khan, N. Muhammad, P. Liu, M.-L. Haymon, F. Rueschendorf, I.-K. Kong, L. Schnapp, N. Shur, L. Chorich, L. Layman, T. Haaf, E. Pourkarimi, H.-G. Kim, G.K. Varshney, Human Mutation 43 (2022) 1472–1489. Lin S-J, Vona B, Porter HM, et al. Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function. Human Mutation. 2022;43(10):1472-1489. doi:<a href="https://doi.org/10.1002/humu.24435">10.1002/humu.24435</a> S.-J. Lin et al., “Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function,” Human Mutation, vol. 43, no. 10. Wiley, pp. 1472–1489, 2022. 143562023-09-20T20:58:24Z2023-09-25T08:54:14Z