{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T14:22:48Z","timestamp":1747146168191,"version":"3.40.5"},"reference-count":23,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T00:00:00Z","timestamp":1639699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy characterized by epileptic seizures, macrocephaly, and vacuolization of myelin and astrocyte. The magnetic resonance imaging of the brain of MLC patients shows diffuse white\u2010matter anomalies and the occurrence of subcortical cysts. MLC features have been observed in individuals having mutations in the <jats:italic>MLC1<\/jats:italic> or <jats:italic>HEPACAM<\/jats:italic> genes. In this study, we recruited a six generation large kindred with five affected individuals manifesting clinical features of epileptic seizures, macrocephaly, ataxia, and spasticity. In order to identify the underlying genetic cause of the clinical features, we performed whole\u2010genome genotyping using Illumina microarray followed by detection of loss of heterozygosity (LOHs) regions. One affected individual was exome sequenced as well. Homozygosity mapping detected several LOH regions due to extensive consanguinity. An unbiased and hypothesis\u2010free exome data analysis identified a homozygous missense variant (NM_015166.3:c.278C&gt;T) in the exon 4 of the <jats:italic>MLC1<\/jats:italic> gene. The variant is present in the LOH region on chromosome 22q (50\u2009Mb) and segregates perfectly with the disorder within the family in an autosomal recessive manner. The variant is present in a highly conserved first cytoplasmic domain of the MLC1 protein (NM_015166.3:p.(Ser93Leu)). Interestingly, heterozygous individuals show seizure and mild motor function deterioration. We propose that the heterozygous variant in <jats:italic>MLC1<\/jats:italic> might disrupt the functional interaction of MLC1 with GlialCAM resulting in mild clinical features in carriers of the variant.<\/jats:p>","DOI":"10.1002\/ajmg.a.62614","type":"journal-article","created":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T10:47:05Z","timestamp":1639738025000},"page":"1075-1082","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A homozygous missense variant in the <i>MLC1<\/i> gene underlies megalencephalic leukoencephalopathy with subcortical cysts in large kindred: Heterozygous carriers show seizure and mild motor function deterioration"],"prefix":"10.1002","volume":"188","author":[{"given":"Syeda","family":"Ain ul Batool","sequence":"first","affiliation":[{"name":"Department of Biotechnology University of Azad Jammu and Kashmir  Muzaffarabad 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