{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:09:21Z","timestamp":1788772161294,"version":"build-2803163510"},"reference-count":24,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:00:00Z","timestamp":1788566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: Biallelic loss-of-function variants in LAMC3, encoding laminin gamma-3, cause occipital cortical malformation (OMIM#614115). White matter disease and intracranial neoplasia have not been reported in this spectrum. We report a novel homozygous LAMC3 frameshift variant, expanding its phenotypic and molecular spectrum. Methods: Two adolescent siblings from a consanguineous Turkish family underwent whole-exome sequencing, with segregation confirmed by NGS\/IGV and classification per ACMG\/AMP criteria. In silico analyses included multiple sequence alignment, AlphaFold modeling of wild-type and mutant proteins, and docking against nidogen-1 (NID1). Results: Both siblings had a novel homozygous LAMC3 variant frameshift variant (NM_006059.4: c.1852_1882del; p.(Pro618Serfs*5)), classified as pathogenic (PVS1, PM2, PP3, PP1) with full cosegregation. Proband II.III, a 17-year-old female, developed postoperative epilepsy after resection of a tectal low-grade glioneuronal tumor harboring a somatic KRAS (NM_004985.3) p.(Gln61Lys) variant (VAF 42.9%), with periventricular white matter gliosis. Proband II.IV, a 15-year-old male, presented with confluent leukoencephalopathy, occipital pachygyria, parietal polymicrogyria, and subcortical band heterotopia, illustrating striking intrafamilial discordance. Conclusions: Docking analysis revealed that the cleavage removes the C-terminal nidogen-binding region, eliminates the predicted wild-type interface (residues 906\u20131029), and shifts the binding to an unnatural N-terminal surface. This finding is a hypothesis-generating result consistent with loss of function. This study expands the LAMC3 phenotype to include leukoencephalopathy and reports a co-occurring low-grade tectal glioneuronal tumor as a novel, single-case observation, supporting inclusion of LAMC3 in the differential diagnosis of pediatric leukoencephalopathies, particularly with consanguinity.<\/jats:p>","DOI":"10.3390\/life16091485","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Homozygous LAMC3 Frameshift Variant Associated with Confluent Leukoencephalopathy and Low-Grade Tectal Glioneuronal Tumor: Expanding the Phenotypic Spectrum with Bioinformatic Characterization"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-431X","authenticated-orcid":false,"given":"Serdar","family":"Bozlak","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Biruni University, Istanbul 34460, Turkey"},{"name":"Department of Pediatric Genetics, University of Health Sciences Basaksehir Cam and Sakura City Hospital, Istanbul 34480, 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guidelines","volume":"143","author":"Severino","year":"2020","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/ng.836","article-title":"Recessive LAMC3 mutations cause malformations of occipital cortical development","volume":"43","author":"Barak","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Falcicchio, G., Riva, A., La Neve, A., Iacomino, M., Lastella, P., Suppressa, P., Sciruicchio, V., Trojano, M., and Striano, P. (2022). Case report: LAMC3-associated cortical malformations: Case report of a novel stop-gain variant and literature review. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.990350"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s10048-017-0534-4","article-title":"A novel mutation in LAMC3 associated with generalized polymicrogyria of the cortex and epilepsy","volume":"19","author":"Zambonin","year":"2018","journal-title":"Neurogenetics"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"De Angelis, C., Byrne, A.B., Morrow, R., Feng, J., Ha, T., Wang, P., Schreiber, A.W., Babic, M., Taranath, A., and Manton, N. (2021). Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-00911-4"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1212\/WNL.0000000000002404","article-title":"Multiplex families with epilepsy: Success of clinical and molecular genetic characterization","volume":"86","author":"Afawi","year":"2016","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1002\/ajmg.a.61846","article-title":"A novel splice variant expands the LAMC3-associated cortical phenotype to frontal only polymicrogyria and adult-onset epilepsy","volume":"182","author":"Kasper","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Qian, X., Liu, X., Zhu, Z., Wang, S., Song, X., Chen, G., Wu, J., Cao, Y., Luan, X., and Tang, H. (2021). Variants in LAMC3 Causes Occipital Cortical Malformation. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.616761"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e680","DOI":"10.1212\/NXG.0000000000000680","article-title":"A New Case With Cortical Malformation Caused by Biallelic Variants in LAMC3","volume":"8","author":"Abe","year":"2022","journal-title":"Neurol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1002\/epd2.20244","article-title":"Novel LAMC3 pathogenic variant enriched in Finnish population causes malformations of cortical development and severe epilepsy","volume":"26","author":"Saarela","year":"2024","journal-title":"Epileptic Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1038\/s41596-020-0312-x","article-title":"The HDOCK server for integrated protein-protein docking","volume":"15","author":"Yan","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/s41580-019-0138-y","article-title":"Publisher Correction: Quality and quantity control of gene expression by nonsense-mediated mRNA decay","volume":"20","author":"Kurosaki","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/s41588-019-0517-5","article-title":"The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy","volume":"51","author":"Lindeboom","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/nature01873","article-title":"Complex between nidogen and laminin fragments reveals a paradigmatic beta-propeller interface","volume":"424","author":"Takagi","year":"2003","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/dneu.22057","article-title":"beta2 and gamma3 laminins are critical cortical basement membrane components: Ablation of Lamb2 and Lamc3 genes disrupts cortical lamination and produces dysplasia","volume":"73","author":"Radner","year":"2013","journal-title":"Dev. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s00441-009-0838-2","article-title":"Laminins","volume":"339","author":"Durbeej","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s00401-019-02112-x","article-title":"Tectal glioma harbors high rates of KRAS G12R and concomitant KRAS and BRAF alterations","volume":"139","author":"Chiang","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2400174","DOI":"10.1200\/PO.24.00174","article-title":"MEK Inhibition in a Pilocytic Astrocytoma with a Rare KRAS Q61R Mutation in a Young Adult Patient: A Case Report","volume":"8","author":"Roberto","year":"2024","journal-title":"JCO Precis. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e228128","DOI":"10.1136\/bcr-2018-228128","article-title":"Unusual KRAS missense mutation (p.E63K) in patient with juvenile pilocytic astrocytoma of the tectum","volume":"12","author":"Chau","year":"2019","journal-title":"BMJ Case Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1007\/s11033-026-11971-z","article-title":"Somatic mutation profiling by NGS-based liquid biopsy in advanced non-small cell lung cancer: Frequency, clinical correlates, and prognostic significance","volume":"53","author":"Dogan","year":"2026","journal-title":"Mol. Biol. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2241","DOI":"10.1002\/brb3.2241","article-title":"Cortical connectivity in the face of congenital structural changes-A case of homozygous LAMC3 mutation","volume":"11","author":"Demirayak","year":"2021","journal-title":"Brain Behav."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.neuroimage.2018.03.077","article-title":"Homozygous LAMC3 mutation links to structural and functional changes in visual attention networks","volume":"190","author":"Urgen","year":"2019","journal-title":"Neuroimage"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/9\/1485\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:26:29Z","timestamp":1788769589000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/9\/1485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,5]]},"references-count":24,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["life16091485"],"URL":"https:\/\/doi.org\/10.3390\/life16091485","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,5]]}}}