Relevance to Autism

In a screen of 44 genes in 2,446 ASD probands from the Simons Simplex Collection, PMID 23160955 found a de novo LoF mutation in TBL1XR1. A second de novo LoF variant in this gene was identified in a patient from the Deciphering Developmental Disorders (DDD study) presenting with autism and developmental delay (PMID 26740553). A number of de novo missense variants in this gene, including several predicted by computer modelling to disrupt protein folding, have also been identified in patients with autism and/or developmental delay (PMIDs 23160955, 26740553). A recurrent de novo missense variant in TBL1XR1 (p.Tyr446Cys) was identified in six unrelated individuals with Pierpont syndrome (OMIM 602342), a syndrome characterized by developmental delay/intellectual disability, facial dysmorphisms, hearing loss, and abnormal fat distribution (PMID 26769062); however, autism has not been detected in individuals with this syndrome. Kruusvee et al., 2017 demonstrated that two de novo missense variants in TBL1XR1 that had been identified in patients from the DECIPHER database presenting with autism and developmental delay/intellectual disability showed impaired binding to MECP2. An additional de novo likely gene-disruptive variant in TBL1XR1 was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified TBL1XR1 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified TBL1XR1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene is a member of the WD40 repeat-containing gene family and shares sequence similarity with transducin (beta)-like 1X-linked (TBL1X). The protein encoded by this gene is thought to be a component of both nuclear receptor corepressor (N-CoR) and histone deacetylase 3 (HDAC 3) complexes, and is required for transcriptional activation by a variety of transcription factors. Mutations in these gene have been associated with some autism spectrum disorders, and one finding suggests that haploinsufficiency of this gene may be a cause of intellectual disability with dysmorphism.

External Links

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