QARS1 associated developmental epileptic encephalopathy: first report of a rare homozygous missense variant from Pakistan causing nonepileptic phenotype in a family of seven patients and a comprehensive review of the literature.

backgroundPathogenic variants in QARS1 (MIM:603727; Glutaminyl-TRNA Synthetase 1), which encodes Glutaminyl-tRNA synthetase 1, have been associated with rare progressive microcephaly with seizures and cerebral and cerebellar atrophy (MSCCA MIM:615760). Only a handful of MSCCA patients have been reported in the literature mostly associated with compound heterozygous QARS1 variants. In the current study, we aimed molecular characterization of a large consanguineous Pakistani family affected with microcephaly, severe intellectual and developmental disability.

methodsWe isolated genomic DNA from blood samples collected from the two affected and three normal individuals of the family. We employed whole exome sequencing, homozygosity mapping, Sanger sequencing and in silico protein modelling tools to characterize the pathogenic variant causing the disease phenotype. Moreover, we collected data of 26 MSCCA patients previously reported in the literature.

resultsThe phenotype in the affected individuals of the family was characterized by microcephaly, severe intellectual and developmental disability, but no epilepsy. We found a rare QARS1 variant NM_005051.3:c.1133G > A, p.(Arg378His) in homozygous state in the family. This variant was recently cited in a patient of Turkish ethnicity, the only MSCCA patient reported with nonepileptic phenotype. This variant lying in the catalytic domain of glutaminyl-tRNA synthetase 1 showed deleterious structure and functional impacts on the protein predicted by in silico tools. The variant was classified as 'likely pathogenic' following ACMG guidelines.

conclusionsWe present first report of QARS1 associated developmental encephalopathy from Pakistan. Our study adds to the restricted clinical and mutational database of this rare disorder supporting the growing evidence that homozygous missense QARS1 genotypes may lead to the milder phenotype. The reports of more patients with molecular studies will enhance the understanding of the genotype-phenotype correlations.