{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:13:48Z","timestamp":1760145228813,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T00:00:00Z","timestamp":1719273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Introduction: The NPRL3 gene is a critical component of the GATOR1 complex, which negatively regulates the mTORC1 pathway, essential for neurogenesis and brain development. Located on chromosome 16p13.3, NPRL3 is situated near the \u03b1-globin gene cluster. Haploinsufficiency of NPRL3, either by deletion or a pathogenic variant, is associated with a variable phenotype of focal epilepsy, with or without malformations of cortical development, with known decreased penetrance. Case Description: This work details the diagnostic odyssey of a neurotypical 10-year-old boy who presented at age 2 with unusual nocturnal episodes and a history of microcytic anemia, as well as a review of the existing literature on NPRL3-related epilepsy, with an emphasis on individuals with deletions who also present with \u03b1-thalassemia trait. The proband\u2019s episodes were mistaken for gastroesophageal reflux disease for several years. He had molecular testing for his \u03b1-thalassemia trait and was noted to carry a deletion encompassing the regulatory region of the \u03b1-thalassemia gene cluster. Following the onset of overt focal motor seizures, genetic testing revealed a heterozygous loss of NPRL3, within a 106 kb microdeletion on chromosome 16p13.3, inherited from his mother. This deletion encompassed the entire NPRL3 gene, which overlaps the regulatory region of the \u03b1-globin gene cluster, giving him the dual diagnosis of NPRL3-related epilepsy and \u03b1-thalassemia trait. Brain imaging postprocessing showed left hippocampal sclerosis and mid-posterior para-hippocampal focal cortical dysplasia, leading to the consideration of epilepsy surgery. Conclusions: This case underscores the necessity of early and comprehensive genetic assessments in children with epilepsy accompanied by systemic features, even in the absence of a family history of epilepsy or a developmental delay. Recognizing phenotypic overlaps is crucial to avoid diagnostic delays. Our findings also highlight the impact of disruptions in regulatory regions in genetic disorders: any individual with full gene deletion of NPRL3 would have, at a minimum, \u03b1-thalassemia trait, due to the presence of the major regulatory element of \u03b1-globin genes overlapping the gene\u2019s introns.<\/jats:p>","DOI":"10.3390\/genes15070836","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T03:42:30Z","timestamp":1719546150000},"page":"836","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Alpha-Thalassemia Trait to NPRL3-Related Epilepsy: A Genomic Diagnostic Odyssey"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6317-4890","authenticated-orcid":false,"given":"Maryam","family":"Nabavi Nouri","sequence":"first","affiliation":[{"name":"Division of Neurology, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada"},{"name":"Children\u2019s Health Research Institute, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lama","family":"Alandijani","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalene","family":"van Engelen","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soumitra","family":"Tole","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilie","family":"Lalonde","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tugce B.","family":"Balci","sequence":"additional","affiliation":[{"name":"Children\u2019s Health Research Institute, London Health Sciences Centre, London, ON N6A 5W9, Canada"},{"name":"Division of Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhang, H., Deng, J., Wang, X., Chen, C., Chen, S., Dai, L., and Fang, F. 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