{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:04:29Z","timestamp":1784822669367,"version":"3.55.0"},"reference-count":12,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Next-generation sequencing has transformed the diagnostic approach to rare neurogenetic disorders. However, interpretation of molecular findings remains challenging when identified variants are discordant with the clinical phenotype. We report the case of a preschool-aged girl presenting with seizures, infantile-onset macrocephaly, and the characteristic magnetic resonance imaging (MRI) pattern of megalencephalic leukoencephalopathy with subcortical cysts (MLC). Whole-exome sequencing identified no pathogenic variants in the currently recognized MLC-associated genes. Instead, it detected a heterozygous SMARCA2 splice-site variant that was classified as \u201clikely pathogenic\u201d by the testing laboratory according to the American College of Medical Genetics and Genomics criteria. However, the patient\u2019s overall clinical presentation was not consistent with the currently recognized spectrum of SMARCA2-related disorders. Comprehensive genotype\u2013phenotype correlation together with a two-year follow-up ultimately supported a diagnosis of classic MLC despite the discordant SMARCA2 finding. This case highlights that molecular findings should complement, rather than override, established clinicoradiological evidence, particularly in disorders with highly characteristic imaging phenotypes.<\/jats:p>","DOI":"10.3390\/diagnostics16152314","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:05:42Z","timestamp":1784819142000},"page":"2314","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diagnostic Pitfall in Genomic Era: Discordant SMARCA2 Finding in Patient with Megalencephalic Leukoencephalopathy with Subcortical Cysts"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0901-0654","authenticated-orcid":false,"given":"Chih-Hao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, MacKay Children\u2019s Hospital, Taipei 104217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuan-Pei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 104217, Taiwan"},{"name":"School of Medicine, College of Medicine, MacKay Medical University, New Taipei City 252005, Taiwan"},{"name":"International Rare Disease Center, MacKay Memorial Hospital, Taipei 104217, Taiwan"},{"name":"Division of Genetics and Metabolism, Department of Medical Research, MacKay Memorial Hospital, Taipei 104217, Taiwan"},{"name":"Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei 108306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon-Kway","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiology, MacKay Memorial Hospital, Taipei 104217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3966-5021","authenticated-orcid":false,"given":"Nan-Chang","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 104217, Taiwan"},{"name":"School of Medicine, College of Medicine, MacKay Medical University, New Taipei City 252005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1395","DOI":"10.1212\/WNL.0000000000005334","article-title":"Megalencephalic leukoencephalopathy with subcortical cysts","volume":"90","author":"Hamilton","year":"2018","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Passchier, E.M.J., Bisseling, Q., Helman, G., van Spaendonk, R.M.L., Simons, C., Olsthoorn, R.C.L., van der Veen, H., Abbink, T.E.M., van der Knaap, M.S., and Min, R. (2024). Megalencephalic leukoencephalopathy with subcortical cysts: A variant update and review of the literature. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1352947"},{"key":"ref_3","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (2023). Megalencephalic Leukoencephalopathy with Subcortical Cysts. GeneReviews\u00ae, University of Washington, Seattle."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_5","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (2025). SMARCA2-Related Nicolaides-Baraitser Syndrome. 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Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1038\/s41436-020-0898-y","article-title":"De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome","volume":"22","author":"Cappuccio","year":"2020","journal-title":"Genet. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e1763","DOI":"10.1002\/mgg3.1763","article-title":"Low-level germline mosaicism of a novel SMARCA2 missense variant: Expanding the phenotypic spectrum and mode of genetic transmission","volume":"9","author":"Pan","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.molcel.2019.06.024","article-title":"Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4","volume":"75","author":"Gao","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1055\/s-0041-1722878","article-title":"Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects","volume":"52","author":"Hofmeister","year":"2021","journal-title":"Neuropediatrics"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/15\/2314\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:16:20Z","timestamp":1784819780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/15\/2314"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":12,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["diagnostics16152314"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16152314","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]}}}