{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T23:41:36Z","timestamp":1773963696069,"version":"3.50.1"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100010221","name":"Higher Education Commision, Pakistan","doi-asserted-by":"publisher","award":["IRSIP 52 BMS 22"],"award-info":[{"award-number":["IRSIP 52 BMS 22"]}],"id":[{"id":"10.13039\/501100010221","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Biol Rep"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in\n                      <jats:italic>QARS1<\/jats:italic>\n                      (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\n                      <jats:italic>QARS1<\/jats:italic>\n                      variants. In the current study, we aimed molecular characterization of a large consanguineous Pakistani family affected with microcephaly, severe intellectual and developmental disability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The phenotype in the affected individuals of the family was characterized by microcephaly, severe intellectual and developmental disability, but no epilepsy. We found a rare\n                      <jats:italic>QARS1<\/jats:italic>\n                      variant NM_005051.3:c.1133G\u2009&gt;\u2009A, 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 \u2018likely pathogenic\u2019 following ACMG guidelines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We present first report of\n                      <jats:italic>QARS1<\/jats:italic>\n                      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\n                      <jats:italic>QARS1<\/jats:italic>\n                      genotypes may lead to the milder phenotype. The reports of more patients with molecular studies will enhance the understanding of the genotype-phenotype correlations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11033-025-10574-4","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T07:06:39Z","timestamp":1748675199000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["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"],"prefix":"10.1007","volume":"52","author":[{"given":"Riaz","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Naeem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"issue":"4","key":"10574_CR1","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.ajhg.2014.03.003","volume":"94","author":"X Zhang","year":"2014","unstructured":"Zhang X, Ling J, Barcia G, Jing L, Wu J, Barry BJ, Mochida GH, Hill RS, Weimer JM, Stein Q, Poduri A (2014) Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. 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