The SOX3 gene is located on the X chromosome at Xq27.1 and encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. SOX3 was first reported in relation to SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder in 2002 (Laumonnier et al., PMID: 12428212, MONDO:0800474). This X-linked inherited disease is characterized by growth hormone deficiency due to hypopituitarism and in some cases intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities panhypopituitarism, X-linked (OMIM: 312000) and intellectual developmental disorder, X-linked, with isolated growth hormone deficiency (OMIM: 300123) have been lumped and are included in this curation. Whereas, 46,XX sex reversal 3 (MONDO:0010442), X-linked congenital generalized hypertrichosis (ORPHA:79495) and Septo-optic dysplasia spectrum (ORPHA:3157) have been split. At least 7 variants including 2 missense, 1 frameshift, 4 in-frame polyA indels have been reported in 8 probands in 7 publications (PMIDs: 30125608, 29175558, 35295983, 21289259, 15800844, 19654509, 12428212) and are included in this curation. The mechanism of pathogenicity appears to be gain of function for polyA in-frame deletion variants and loss of function for polyA in-frame insertion variants. This gene-disease association is also supported by expression and protein-protein interaction with HESX1 (PMID: 15800844), which is associated with pituitary hormone deficiency (PMID: 27000987). Also included is a conditional knockout mouse model which demonstrates lower levels of pituitary growth hormone, luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormone (PMID: 14981518). In summary, there is moderate evidence supporting the relationship between SOX3 and X-linked pituitary hormone deficiency with or without intellectual developmental disorder (MONDO:0800474). While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 08/02/23 (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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