The GSX2 gene encodes a transcription factor thought to be involved in brain development. GSX2 was first reported in relation to autosomal recessive Diencephalic-Mesencephalic Junction Dysplasia Syndrome 2 in 2019 (De Mori et al., PMID: 31412107). Phenotypes onset at birth and can include severe global developmental delay, spastic tetraplegia, abnormal basal ganglia morphology, dystonia, decreased thalamic volume, absent speech, feeding difficulties in infancy, inability to walk, and hypoplasia of the olfactory bulb. Evidence supporting this gene-disease relationship include case-level data and experimental data. The genetic evidence in this curation includes two variants, one nonsense and one missense, from two probands, reported in one publication (De Mori et al., PMID: 31412107). The mechanism of disease is presumed to be reduced or loss of function. This gene-disease relationship is also supported by experimental evidence. A GSX2 knockout mouse model demonstrated a reduced lateral ganglionic eminence size in the forebrain at developmental stages E12.5 to E17.5, similar to basal ganglia agenesis observed in patients (PMID: 9398437).
In summary, there is limited evidence supporting the relationship between GSX2 and autosomal recessive Diencephalic-Mesencephalic Junction Dysplasia Syndrome 2. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on February 27, 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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