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

Version 2 2024-06-26, 11:11
Version 1 2024-06-26, 11:09
journal contribution
revised on 2024-06-26, 11:11 and posted on 2024-06-26, 11:11 authored by Sheng‐Jia Lin, Barbara Vona, Hillary M. Porter, Mahmoud Izadi, Kevin Huang, Yves Lacassie, Jill A. Rosenfeld, Saadullah Khan, Cassidy Petree, Tayyiba A. Ali, Nazif Muhammad, Sher A. Khan, Noor Muhammad, Pengfei Liu, Marie‐Louise Haymon, Franz Rüschendorf, Il‐Keun Kong, Linda Schnapp, Natasha Shur, Lynn Chorich, Lawrence Layman, Thomas Haaf, Ehsan Pourkarimi, Hyung‐Goo Kim, Gaurav K. Varshney

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.

Other Information

Published in: Human Mutation
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1002/humu.24435

Funding

Open Access funding provided by by Projekt DEAL.

Oklahoma Medical Research Foundation (PHF-4411-07-04-0).

Deutsche Forschungsgemeinschaft (469177153), Hereditary hearing loss: from gene to mechanism.

National Research Foundation of Korea (2020R1A2C2006614).

Hamad Bin Khalifa University, Qatar Biomedical Research Institute.

Caenorhabditis Genetics Center (P40 OD010440).

Oklahoma Medical Research Foundation and Presbyterian Health Foundation (PHF-4411-07-04-0).

History

Language

  • English

Publisher

Hindawi

Publication Year

  • 2022

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Qatar Biomedical Research Institute - HBKU
  • Neurological Disorders Research Center - QBRI

Related Datasets

Barbara Vona. (2022). Variant #0000846763 (NC_000014.8:g.100835522T>C, NM_004184.3:c.1A>G (WARS)). Last modified 2022. Leiden University Medical Center : Leiden Open Variation Database (LOVD v.3.0). https://databases.lovd.nl/shared/variants/0000846763#00022706 Barbara Vona. (2022). Variant #0000846766 (NC_000014.8:g.100835522T>C, NM_004184.3:c.1A>G (WARS)). Last modified 2022. Leiden University Medical Center : Leiden Open Variation Database (LOVD v.3.0). https://databases.lovd.nl/shared/variants/0000846766#00022706 Barbara Vona. (2022). Variant #0000846767 (NC_000014.8:g.100801373C>T, NM_004184.3:c.1255G>A (WARS)). Last modified 2022. Leiden University Medical Center : Leiden Open Variation Database (LOVD v.3.0). https://databases.lovd.nl/shared/variants/0000846767#00022706