@article{14356,
  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.},
  author       = {Lin, Sheng-Jia and Vona, Barbara and Porter, Hillary M. and Izadi, Mahmoud and Huang, Kevin and Lacassie, Yves and Rosenfeld, Jill A. and Khan, Saadullah and Petree, Cassidy and Ali, Tayyiba A. and Muhammad, Nazif and Khan, Sher A. and Muhammad, Noor and Liu, Pengfei and Haymon, Marie-Louise and Rueschendorf, Franz and Kong, Il-Keun and Schnapp, Linda and Shur, Natasha and Chorich, Lynn and Layman, Lawrence and Haaf, Thomas and Pourkarimi, Ehsan and Kim, Hyung-Goo and Varshney, Gaurav K.},
  issn         = {1059-7794},
  journal      = {Human Mutation},
  keywords     = {autosomal recessive, biallelic variants, C, elegans, translation initiation sites, tryptophanyl-tRNA synthetase 1 (WARS1), WHEP domain, zebrafish},
  number       = {10},
  pages        = {1472--1489},
  publisher    = {Wiley},
  title        = {{Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function}},
  doi          = {10.1002/humu.24435},
  volume       = {43},
  year         = {2022},
}