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Updated: Jul 8, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike-and-wave
Laura Licchetta1, Lucia Di Giorgi1,2, Margherita Santucci3
1IRCCS Istituto delle Scienze Neurologiche di Bologna, Full member of the European Reference Network EpiCARE Bologna, Bologna, Italy.
Background:
Biallelic pathogenic variants in the mitochondrial prolyl-tRNA synthetase 2 gene (PARS2, OMIM * 612036) have been associated with Developmental and Epileptic Encephalopathy-75 (DEE-75, MIM #618437). This condition is typically characterized by early-onset refractory infantile spasms with hypsarrhythmia, intellectual disability, microcephaly, cerebral atrophy with hypomyelination, lactic acidemia, and cardiomyopathy. Most affected individuals do not survive beyond the age of 10 years.
Methods:
We describe a patient with early-onset DEE, consistently showing an EEG pattern of Spike-and-Wave Activation in Sleep (SWAS) since childhood. The patient underwent extensive clinical, metabolic and genetic investigations, including whole exome sequencing (WES).
Results:
WES analysis identified compound heterozygous variants in PARS2 that have been already reported as pathogenic. A literature review of PARS2-associated DEE, focusing mainly on the electroclinical phenotype, did not reveal the association of SWAS with pathogenic variants in PARS2. Notably, unlike previously reported cases with the same genotype, this patient had longer survival without cardiac involvement or lactic acidosis, suggesting potential genetic modifiers contributing to disease variability.
Conclusion:
These findings widen the genetic heterogeneity of DEE-SWAS, including PARS2 as a causative gene in this syndromic entity, and highlight the importance of prolonged sleep EEG recording for the recognition of SWAS as a possible electroclinical evolution of PARS2-related DEE.
Insights
This study identifies pathogenic variants in the PARS2 gene causing Developmental and Epileptic Encephalopathy with Spike-and-Wave Activation in Sleep (DEE-SWAS). It highlights PARS2 as a novel genetic cause for DEE-SWAS, expanding diagnostic possibilities.
Area of Science:
- Genetics
- Neuroscience
- Pediatrics
Background:
- Biallelic pathogenic variants in the mitochondrial prolyl-tRNA synthetase 2 gene (PARS2) are linked to Developmental and Epileptic Encephalopathy-75 (DEE-75).
- DEE-75 typically presents with early-onset seizures, intellectual disability, microcephaly, and often has a poor prognosis, with most patients not surviving past age 10.
- Key features include refractory infantile spasms, hypsarrhythmia, cerebral atrophy, hypomyelination, lactic acidosis, and cardiomyopathy.
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