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The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy


Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a family of enzymes that play critical roles in protein biosynthesis. Mutations in mt-aaRSs are associated with various diseases. As a member of the mt-aaRS family, PARS2 encoding prolyl-tRNA synthetase 2 was recently shown to be associated with Alpers syndrome and certain infantile-onset neurodegenerative disorders in four patients. Here, we present two patients in a pedigree with early developmental delay, epileptic spasms, delayed myelination combined with cerebellar white matter abnormalities, and progressive cortical atrophy. Whole-exome sequencing revealed pathogenic compound heterozygous variants [c.283 G > A (p.95 V > I)] and [c.604 G > C (p.202 R > G)] in PARS2. Nearly all patients had epileptic spasms with early response to treatment, early developmental delay and/or regression followed by generalized hypotonia, postnatal microcephaly, elevated lactate levels, and progressive cerebral atrophy. Our study provides further evidence for validating the role of PARS2 in the pathology of related infantile-onset encephalopathy, contributing to the phenotypic features of this condition, and providing clinical and molecular insight for the diagnosis of this disease entity.

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We are indebted to all the patients and family members for their generous participation in this work. We also thank all the clinicians (including pediatricians), laboratory scientists, and bioinformaticians for discussion on the interpretation of sequencing variants. Many thanks go in particular to Ph.D. Ananya Ray-Soni at the Massachusetts General Hospital, Harvard Medical School and Ph.D. Arif Muhammad at Center for Medical Genetics, Central South University, for their suggestions, language editing and proofreading. This work was supported by the National Natural Science Foundation of China [grant numbers 81300980, 81130021, and 81601119].

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Correspondence to Nan Li.

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Yin, X., Tang, B., Mao, X. et al. The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy. J Hum Genet 63, 971–980 (2018).

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