TFE3 variants were first reported in connection with X-linked syndromic complex neurodevelopmental disorder in 2019 by a program designed to identify genetic casualties of Hypomelanosis of Ito (Villegas et al., 2019; PMID: 30595499). Affected individuals are characterized by a phenotypic triad of severe developmental delay, coarse facial dysmorphisms, and Blaschkoid pigmentary mosaicism. Additional clinical features may include epilepsy, orthopedic abnormalities, hypotonia, and growth abnormalities.
Thirteen de novo variants (12 missense, 1 canonical splice site) reported in four publications were included in this curation (PMIDs: 30595499, 31833172, 32409512, 35503477). One variant has been reported at a mosaic state in at least two male patients. Thus far, TFE3 variants causative of the disorder are located in exons 3 and 4. Functional evidence indicates that the absence of either TFE3 exon 3 or 4 results in a nuclear gain-of-function Tfe3 allele in Embryonic Stem Cells (ESCs), indicating that both exons are required for Tfe3 inactivation (PMID: 30595499). The maximum score for genetic evidence (12 pts.) has been reached.
No convincing experimental evidence supports this gene-disease relationship. Tfe3 KO mice demonstrate significant abnormalities in energy balance and alterations in systemic glucose and lipid metabolism, resulting in enhanced diet‐induced obesity and diabetes (PMID: 28283651). Metabolic anomalies are observed in patients affected by this disorder, suggesting that the gene may be important for metabolic signaling and lipid metabolism in both mice and humans. However, due to lack of construct validity (the difference in mechanism of pathogenicity between mice and humans), this mouse model was not scored.
In summary, there is Definitive evidence to support the relationship between TFE3 and X-linked syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism expert panel on March 19th, 2024 (SOP Version 10).
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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