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| Item Type: | Article |
|---|---|
| Title: | Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function |
| Creators Name: | Lin, S.J. and Vona, B. and Porter, H.M. and Izadi, M. and Huang, K. and Lacassie, Y. and Rosenfeld, J.A. and Khan, S. and Petree, C. and Ali, T.A. and Muhammad, N. and Khan, S.A. and Muhammad, N. and Liu, P. and Haymon, M.L. and Rüschendorf, F. and Kong, I.K. and Schnapp, L. and Shur, N. and Chorich, L. and Layman, L. and Haaf, T. and Pourkarimi, E. and Kim, H.G. and Varshney, G.K. |
| 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 C. 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. This article is protected by copyright. All rights reserved. |
| Keywords: | Autosomal Recessive, Biallelic Variants, Tryptophanyl-tRNA Synthetase 1 (WARS1), Translation Initiation Sites, WHEP Domain |
| Source: | Human Mutation |
| ISSN: | 1059-7794 |
| Publisher: | Wiley |
| Volume: | 43 |
| Number: | 10 |
| Page Range: | 1472-1489 |
| Date: | October 2022 |
| Official Publication: | https://doi.org/10.1002/humu.24435 |
| PubMed: | View item in PubMed |
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