MLC1 was first reported in relation to autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts 1 in 2001(Leegwater et al., PMID: 11254442). Prior to this in 2000, (Topçu et al., PMID: 10677334) the location of the gene was mapped to Chromosome 22qtel.
Prior to the identification of the gene, the condition was first clinically described in 1995 (Van der Knaap et al., PMID: 7695231). A group of 8 children were described with infantile onset megaloencepahly and cerebral leukodystrophy with slowly progressive ataxia and spasticity. Brain MRI were significant for diffuse abnormality in signal intensity and swelling of the cerebral hemispheral white matter with cyst-like spaces in the frontoparietal and anterior-temporal subcortical areas.
Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or inheritance pattern. Therefore, there is one disease entity, Megalencephalic leukoencephalopathy with subcortical cysts 1 (OMIM:604004).
11 variants (missense, nonsense, frameshift,) that have been reported in 9 probands in 5 publications (PMIDs: 25497041, 32056211, 12189496, 21145992, 27389245) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence (functional alteration, expression studies) (PMIDs: 18757878). Lower expression in rat astrocytes and altered pH distribution. In summary, there is definitive evidence supporting the relationship between *MLC1 *and autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP at the meeting November 25, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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