10. New evidence for triplosensitivity of TBL1XR1

      Transducin-beta-like 1 receptor 1 (TBL1XR1), encoded on chromosome 3 at q26.32, is a WD40 domain-containing protein with roles in both transcriptional activation and repression. Missense and loss-of-function sequence variants in TBL1XR1 have been identified in individuals with autism, developmental delay, and/or intellectual disability, as well as Pierpont syndrome, characterized by distinctive facial features, global developmental delay, learning disability, and palmer and plantar fat pads. Additionally, microdeletions involving TBL1XR1 are associated with autosomal dominant intellectual disability with nonspecific dysmorphic facial features. Recently, there has been one report of four individuals with microduplications encompassing TBL1XR1 that presented clinically with speech and developmental delay, learning disability, or mild intellectual disability. The copy number gain was de novo in one individual and was shown to segregate in three affected individuals in another family. Although the duplications are predicted to increase the dosage of TBL1XR1, these individuals were phenotypically similar to microdeletion patients. Furthermore, there are five individuals in the DECIPHER database with autism, delay, and intellectual disability with focal duplications of TBL1XR1. The duplications were shown to be de novo in two of the individuals and segregated in a mother and daughter in another family. Here, we present an additional patient with speech and developmental delay, concern for autism, and a maternal family history of learning difficulties. Using the Affymetrix CytoScan HD microarray system, we identified a heterozygous 288 kb gain of 3q26.32, involving only the TBL1XR1 gene. Parental testing is pending. This is the smallest copy number gain reported thus far that still contains the entire coding region of the TBL1XR1 gene; however, the patient's clinical presentation closely resembles previous reports. Although duplications of this region of chromosome 3 appear to be rare, this case provides further evidence for TBL1XR1 triplosensitivity.
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