Loss of GFAP cause retinal dysplasia and vision impairment

Diagnosis of genetic diseases has taken tremendous steps forward since the human genome project and technical advancements such as next generation sequencing. However, in the past years it has become evident that the classical "one gene - one phenotype" model is insufficient to encompass the intricacies of human genetics. Examples are emerging that variants in a gene can cause quite diverging phenotypes depending on the specific location in the gene or on the specific type of variant. In the era of precision medicine this is important knowledge, both when interpreting genomic data, but also when designing treatment strategies. Gain-of-function variants in GFAP leads to protein aggregation and is the cause of the severe neurodegenerative disorder Alexander Disease (AxD), while loss of GFAP function has been considered benign. Here, we report a loss-of-function variant in GFAP as the cause of optico-retinal dysplasia and vision impairment in a six-generation family. Whole genome sequencing analysis of family members with gliosis of the optic nerve head and visual impairment revealed a frameshift variant in GFAP (c.928dup, p.(Met310Asnfs*113)) segregating with disease. Analysis of human embryonic tissues revealed strong expression of GFAP in retinal neural progenitors. A zebrafish model verified that c.928dup does not result in extensive GFAP protein aggregation and zebrafish gfap loss-of-function mutants showed vision impairment and retinal dysplasia, characterized by a significant loss of Muller glia cells and photoreceptor cells. Our findings show how different mutational mechanisms can cause diverging phenotypes and reveal a novel function of GFAP in human eye development.