Variation in TBR1 was first reported in individuals in relation to autism spectrum disorder in 2014 by Deriziotis et al. (PMID: 25232744). TBR1 has also been associated with intellectual developmental disorder with autism and speech delay (OMIM #606053), 2q24 microdeletion syndrome, occipital pachygyria and polymicrogyria. Since then, phenotypes associated with variants in TBR1 have been expanded and range from autism spectrum disorder, delayed speech and language development, joint hypermobility, severe intellectual disability/global developmental delay, abnormality of the skull, cerebral palsy, etc. (Deriziotis et al., 2014 PMID: 25232744; Huang et al., 2014 PMID: 24441682; Palumbo et al., 2014 PMID:24458984).Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the ID/Autism GCEP decided to lump into one disease entity, complex neurodevelopmental disorder (Mondo:0100038). There are individuals that have been reported with other phenotypes including joint hypermobility and muscle dysfunction. It is unclear at this time whether these phenotypes are related to variants in TBR1 or are due to other circumstances. Most proband information was collected from large case control studies where other phenotypic features are not reported, therefore making the phenotypic profile unclear.
Twenty-six variants (missense, in-frame indel, frameshift) have been included in this curation. These variants have been reported in thirty-two individuals across two publications (PMIDs: 25232744, 32005960).More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be LOF. This gene-disease relationship is also supported by protein interactions, expression studies, animal models, and biochemical function studies (PMIDs: 25232744, 24309898, 10749215, 32005960). In summary, TBR1 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ID/Autism Gene Curation Expert Panel on 03/25/2020.
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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