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

Autor:	Lin SJ; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA., Vona B; Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.; Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Porter HM; Children's National Hospital, Rare Disease Institute, Washington, District of Columbia, USA., Izadi M; Division of Genomics and Translational Medicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar., Huang K; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA., Lacassie Y; 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., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics Laboratories, Houston, Texas, USA., Khan S; Department of Biotechnology and Genetic Engineering, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan., Petree C; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA., Ali TA; Division of Genomics and Translational Medicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar., Muhammad N; Department of Biotechnology and Genetic Engineering, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan., Khan SA; Department of Biotechnology and Genetic Engineering, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan., Muhammad N; Department of Biotechnology and Genetic Engineering, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan., Liu P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics Laboratories, Houston, Texas, USA., Haymon ML; Children Hospital New Orleans Louisiana, Pediatric Radiology, Tulane Associate Professor of Radiology, New Orleans, Los Angeles, USA., Rüschendorf F; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Kong IK; Department of Animal Sciences, Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju, South Korea., Schnapp L; Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany., Shur N; Children's National Hospital, Rare Disease Institute, Washington, District of Columbia, USA., Chorich L; 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., Layman L; 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., Haaf T; Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany., Pourkarimi E; Division of Genomics and Translational Medicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar., Kim HG; Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar., Varshney GK; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Jazyk:	angličtina
Zdroj:	Human mutation [Hum Mutat] 2022 Oct; Vol. 43 (10), pp. 1472-1489. Date of Electronic Publication: 2022 Jul 21.
DOI:	10.1002/humu.24435
Abstrakt:	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. (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)
Databáze:	MEDLINE
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