Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome

Open AccessPublished:December 19, 2022DOI:
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      Transformer2 proteins (Tra2α and Tra2β) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder.


      Twelve individuals from 11 unrelated families who had predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA-seq and Western blot analyses of Tra2β-1 and Tra2β-3 isoforms from patient-derived cells were performed. Tra2β1-GFP, Tra2β3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells.


      All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of non-canonical Tra2β-3 isoform. All of affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2β-1 isoform, while they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1.


      Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein.

      Graphical abstract



      CDS (coding sequence), GFP (Green Fluorescent Protein), PSI (percentage splicing inclusion), RRM (RNA recognition motif), RS domain (arginine serine rich domain), SR protein (serine arginine rich protein), SRRM4 (Serine Arginine Repetitive Matrix 4), Tra2 (Transformer2), Tra2α (Transformer2 alpha homolog protein), Tra2β (Transformer2beta homolog protein), Tra2β-1 (Tra2β protein isoform 1), Tra2β-3 (Tra2β protein isoform 3)