| Contributors: |
Lin, Sheng‐Jia; Vona, Barbara; Porter, Hillary M.; Izadi, Mahmoud; Huang, Kevin; Lacassie, Yves; Rosenfeld, Jill A.; Khan, Saadullah; Petree, Cassidy; Ali, Tayyiba A.; Muhammad, Nazif; Khan, Sher A.; Muhammad, Noor; Liu, Pengfei; Haymon, Marie‐Louise; Rüschendorf, Franz; Kong, Il‐Keun; Schnapp, Linda; Shur, Natasha; Chorich, Lynn; Layman, Lawrence; Haaf, Thomas; Pourkarimi, Ehsan; Kim, Hyung‐Goo; Varshney, Gaurav K.; 1 Genes & Human Disease Research Program Oklahoma Medical Research Foundation Oklahoma City Oklahoma USA; 5 Children's National Hospital Rare Disease Institute Washington District of Columbia USA; 6 Division of Genomics and Translational Medicine, College of Health and Life Sciences Hamad Bin Khalifa University Doha Qatar; 7 Department of Pediatrics, Louisiana State University Health Sciences Center Head Division of Clinical Genetics and Dept. of Genetics Children's Hospital 1986‐2016 New Orleans Los Angeles USA; 8 Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA; 10 Department of Biotechnology and Genetic Engineering Kohat University of Science & Technology Kohat Khyber Pakhtunkhwa Pakistan; 11 Children Hospital New Orleans Louisiana, Pediatric Radiology Tulane Associate Professor of Radiology New Orleans Los Angeles USA; 12Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany; 13 Department of Animal Sciences, Division of Applied Life Science (BK21 Four) Gyeongsang National University Jinju South Korea; 2 Institute of Human Genetics Julius Maximilians University Würzburg Würzburg Germany; 14 Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia Augusta University Augusta USA; 15 Neurological Disorders Research Center, Qatar Biomedical Research Institute Hamad Bin Khalifa University Doha Qatar |
| Description: |
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. ; Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659 ; Qatar Foundation http://dx.doi.org/10.13039/100007458 ; National Research Foundation of Korea http://dx.doi.org/10.13039/501100003725 ; Oklahoma Medical Research Foundation http://dx.doi.org/10.13039/100008907 ; Presbyterian Health Foundation http://dx.doi.org/10.13039/100001298 |