Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function
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.
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Author
Lin, Sheng-Jia;
Vona, Barbara;
Porter, Hillary M.;
Izadi, Mahmoud;
Huang, KevinISTA ;
Lacassie, Yves;
Rosenfeld, Jill A.;
Khan, Saadullah;
Petree, Cassidy;
Ali, Tayyiba A.;
Muhammad, Nazif;
Khan, Sher A.
All
All
Abstract
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.
Keywords
Publishing Year
Date Published
2022-10-01
Journal Title
Human Mutation
Volume
43
Issue
10
Page
1472-1489
ISSN
IST-REx-ID
Cite this
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:10.1002/humu.24435
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. https://doi.org/10.1002/humu.24435
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. https://doi.org/10.1002/humu.24435.
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.
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, 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:10.1002/humu.24435.
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