---
_id: '14356'
abstract:
- lang: eng
text: 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.
article_processing_charge: No
article_type: original
author:
- first_name: Sheng-Jia
full_name: Lin, Sheng-Jia
last_name: Lin
- first_name: Barbara
full_name: Vona, Barbara
last_name: Vona
- first_name: Hillary M.
full_name: Porter, Hillary M.
last_name: Porter
- first_name: Mahmoud
full_name: Izadi, Mahmoud
last_name: Izadi
- first_name: Kevin
full_name: Huang, Kevin
id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3
last_name: Huang
orcid: 0000-0002-2512-7812
- first_name: Yves
full_name: Lacassie, Yves
last_name: Lacassie
- first_name: Jill A.
full_name: Rosenfeld, Jill A.
last_name: Rosenfeld
- first_name: Saadullah
full_name: Khan, Saadullah
last_name: Khan
- first_name: Cassidy
full_name: Petree, Cassidy
last_name: Petree
- first_name: Tayyiba A.
full_name: Ali, Tayyiba A.
last_name: Ali
- first_name: Nazif
full_name: Muhammad, Nazif
last_name: Muhammad
- first_name: Sher A.
full_name: Khan, Sher A.
last_name: Khan
- first_name: Noor
full_name: Muhammad, Noor
last_name: Muhammad
- first_name: Pengfei
full_name: Liu, Pengfei
last_name: Liu
- first_name: Marie-Louise
full_name: Haymon, Marie-Louise
last_name: Haymon
- first_name: Franz
full_name: Rueschendorf, Franz
last_name: Rueschendorf
- first_name: Il-Keun
full_name: Kong, Il-Keun
last_name: Kong
- first_name: Linda
full_name: Schnapp, Linda
last_name: Schnapp
- first_name: Natasha
full_name: Shur, Natasha
last_name: Shur
- first_name: Lynn
full_name: Chorich, Lynn
last_name: Chorich
- first_name: Lawrence
full_name: Layman, Lawrence
last_name: Layman
- first_name: Thomas
full_name: Haaf, Thomas
last_name: Haaf
- first_name: Ehsan
full_name: Pourkarimi, Ehsan
last_name: Pourkarimi
- first_name: Hyung-Goo
full_name: Kim, Hyung-Goo
last_name: Kim
- first_name: Gaurav K.
full_name: Varshney, Gaurav K.
last_name: Varshney
citation:
ama: 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
apa: 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
chicago: 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.
ieee: 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.
ista: 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.
mla: 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.
short: 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.
date_created: 2023-09-20T20:58:24Z
date_published: 2022-10-01T00:00:00Z
date_updated: 2023-09-25T08:54:14Z
day: '01'
ddc:
- '570'
doi: 10.1002/humu.24435
extern: '1'
file:
- access_level: open_access
checksum: 74b01d4e4084b2f64c30ed32b18ee928
content_type: application/pdf
creator: dernst
date_created: 2023-09-25T08:52:54Z
date_updated: 2023-09-25T08:52:54Z
file_id: '14370'
file_name: 2022_HumanMutation_Lin.pdf
file_size: 12131312
relation: main_file
success: 1
file_date_updated: 2023-09-25T08:52:54Z
has_accepted_license: '1'
intvolume: ' 43'
issue: '10'
keyword:
- autosomal recessive
- biallelic variants
- C
- elegans
- translation initiation sites
- tryptophanyl-tRNA synthetase 1 (WARS1)
- WHEP domain
- zebrafish
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
page: 1472-1489
publication: Human Mutation
publication_identifier:
issn:
- 1059-7794
publication_status: published
publisher: Wiley
quality_controlled: '1'
scopus_import: '1'
status: public
title: Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome
and implicate a critical exon for normal auditory function
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 43
year: '2022'
...