Variants in HEPACAM, also known as GLIALCAM, were first reported by Lopez-Hernandez in 2011 (PMID: 21419380) in relation to the autosomal recessive (AR) condition megalencephalic leukoencephalopathy with subcortical cysts, 2A (MLC2A). Variants in this gene are also implicated in an autosomal dominant (AD) condition, megalencephalic leukoencephalopathy with subcortical cysts 2B (MLC2B). AR MLC2A is characterized by early-onset macrocephaly and delayed-onset neurologic deterioration, including cerebellar ataxia, spasticity, epilepsy, and mild cognitive decline. AD MLC2B is characterized by infantile-onset of macrocephaly and mildly delayed motor development related to spontaneously resolving white matter abnormalities. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there are differences in inheritance pattern and phenotypic variability and therefore, these two entities have been split and MLC2B has been curated separately.
Fourteen variants (10 missense, 2 nonsense, and 2 frameshift) been reported in 13 patients from 11 families (PMIDs: 21419380, 24202401, 27389245, 31372844) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached.
HEPACAM is a direct MLC1-binding partner. The mechanisms of pathogenicity include trafficking defects and impaired interaction between GlialCAM and its protein targets (PMID: 21419380, 31960914). This gene-disease relationship is also supported by expression studies, in vitro/in vivo functional assays and animal models. For example, in cultured cells, coexpression of wild-type MLC1 and HEPACAM missense variants resulted in altered localization of MLC1 and mutated HEPACAM (PMID: 21419380, 25044933). Furthermore, mice harboring homozygous GlialCAM G89S variants showed myelin vacuolization in the cerebellum (PMID: 24647135).
In summary, there is definitive evidence to support the relationship between HEPACAM and autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts 2A. 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 Intellectual Disability and Autism Gene Curation Expert Panel on January 12, 2023 (SOP 9).
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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