Heterozygous variants in HEPACAM, also known as GLIALCAM, have been reported in relation to an autosomal dominant (AD) disorder, megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability (MLC2B), the subject of this curation. Bi-allelic variants in this gene have also been reported in relation to the autosomal recessive (AR) disorder, megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A). AD MLC2B is characterized by infantile-onset macrocephaly and mildly delayed motor development related to spontaneously resolving white matter abnormalities. AR MLC2A is characterized by early-onset macrocephaly and delayed onset neurological deterioration including ataxia, spasticity epilepsy and mild cognitive decline. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there are differences in inheritance pattern and phenotypic variability and therefore, the disorders related to HEPACAM have been split into two disease entities. AR MLC2A has been curated separately.
Seven unique variants, including 6 missense and 1 ins/del mutations that have been reported in 22 probands and 3 affected siblings with improving MLC phenotypes in three publications (PMIDs: 21419380, 24202401, 27322623), are included in this curation. Most reported patients inherited their variants from a parent with macrocephaly. The maximum score for genetic evidence (12 pts.) has been reached.
In summary, there is definitive evidence to support the relationship between HEPACAM and autosomal dominant megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability. 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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.