GAS1 was first reported in relation to autosomal dominant holoprosencephaly in 2010 (Ribero et al., PMID: 20583117). GAS1 has been associated with the phenotypic spectrum of holoprosencephaly in the literature and has therefore been curated for this disease relationship. 10 missense variants have been reported in 10 probands in 2 publications (PMIDs: 20583117, 21842183), of which one is included in this curation. The mechanism of pathogenicity appears to be loss o function. GAS1 and SHH have been reported to physically interact with variants in GAS1 suggesting a decrease in SHH downstream signaling cascades (PMID: 17525797). This gene-disease association is also supported by aminal models (PMIDs: 17525797, 17504940). GAS1 -/- mice were observed to recapitulate some phenotypic features of microform holoprosencephaly, midfacial hypoplasia, and cleft palate, in addition to additional craniofacial malformations. Interestingly, Gas1−/−; Shh−/− mice were not found at birth, suggesting embryonic lethality, while Gas1+/−; Shh+/− mice were phenotypically normal. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date 01/10/2023 (SOP Version 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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