Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities
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We describe a family with QARS deficiency due to compound heterozygous QARS mutations, including c.1387G > A (p.R463*) in the catalytic core domain and c.2226C > G (p.Q742H) in the anticodon domain, both previously unreported and predicted damaging. The phenotype of the male index further confirms this specific aminoacyl-transfer RNA (tRNA) synthetase disorder as a novel genetic cause of progressive microcephaly with diffuse cerebral atrophy, severely deficient myelination, intractable seizures, and developmental arrest. However, in contrast to the two hitherto published families, the cerebellum and its myelination are not affected. An awareness that QARS mutations may cause isolated supratentorial changes is crucial for properly directing genetic analysis.
KeywordsEpilepsy Microcephaly Developmental delay Hypomyelination Cerebral atrophy Genomics
We gratefully acknowledge the family for their participation in this study; Dr. M. van der Knaap (Free University Medical Centre, Amsterdam NL) for neuroradiologic evaluation; Dr. R. Burgess (Jackson Laboratory, Maine U.S.A.), Dr. P. Tan and Dr. L. French for expert input regarding candidate genes; Dr. R. Buck for clinical management of the patient; Dr. M. Aroichaine, Dr. J. Gardiner, Dr. C. Lyons, Dr. A. Merkur for ophthalmological evaluation; Mrs. X. Han for Sanger sequencing; Mr. B. Sayson for consenting and data management; Mrs. M. Higginson for DNA extraction, sample handling, and technical data (University of British Columbia, Vancouver, CA).
The authors declare that the experiments comply with the current laws of Canada, the country in which they were performed.
This work was supported by funding from the B.C. Children’s Hospital Foundation as “1st Collaborative Area of Innovation” (www.tidebc.org), Genome BC (SOF-195 grant), the Canadian Institutes of Health Research (#301221 grant), and the British Columbia Clinical Genomics Network [grant number BCCGN00031]. Informatics infrastructure was supported by Genome BC and Genome Canada (ABC4DE Project). CvK is a Michael Smith Foundation for Health Research Scholar.
Conflict of interest
The authors declare that they have no conflict(s) of interest.
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