Submission Details

The association between autosomal dominant Alexander Disease and variants in GFAP first occurred in 2002 (Li et al., PMID:12175861). Alexander disease, a leukodystrophy characterized by protein aggregates called Rosenthal fibers on brain biopsy, is a primary disorder of astrocytes. The GFAP gene encodes glial fibrillary acidic protein, which is the major intermediate filament protein in astrocytes. The clinical characteristics of Alexander Disease include variable age of onset, from neonatal to adult, and clinical manifestations include developmental delay, seizures, megalencephaly, autonomic dysfunction, and gait abnormalities. Twenty-seven missense variants reported in 27 probands across 7 publications (PMIDs: 12034785, 36088400, 35003479, 27648269, 11567214, 16505300, 15732097) are included in this curation. More evidence exists in the literature, but the maximum required score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is gain-of-function. This gene-disease relationship is supported by experimental evidence, including pathology studies and mouse models (PMIDs: 9466565). In summary, definitive evidence supports the relationship between GFAP and autosomal dominant Alexander Disease, with rigorous and reproducible evidence in research and clinical diagnostic settings. This gene-disease curation based on ClinGen criteria was approved by the Leukodystrophy and Leukoencephalopathy GCEP on the meeting date October 23, 2023. (SOP Version 9).