TBR1-related disorder is due to loss of function variants including deletions, frameshift, nonsense, or missense variants. A single in-frame deletion was reported but without associated functional studies.
Functional studies in cellular model systems demonstrated that both missense variants and variants introducing premature stop codons have a deleterious impact on protein function. A dominant-negative effect on function and the localization of the protein was suggested for the missense variants, and a mechanism of haploinsufficiency was suggested for the variants presenting premature stop codons, although conclusive evidence is still lacking.
All the reported TBR1 variants occurred de novo (except for one individual for which it can’t be verified as a result of sperm donation).
It has been shown that inherited missense variants in individuals with ASD probands do not disturb protein function, while de novo heterozygous variants in sporadic ASD lead to protein dysfunction .
No loss of function variant is reported in the GnomAD database, leading to a pLI equal to 1 (one variant observed/24.5 expected). This gene is thus extremely intolerant to LoF variants, but also to missense variants. The z-score in GnomAD is 3.64 (172 variants observed/368.4 expected). Currently, there is no known genotype/phenotype correlation.
TBR1