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

Lorena Santa María, David J Elliott, Tobias Haack, Carlos E Prada, Sabine Hoffjan, Lily Bazak, Ofir Hagari, Noa Ruhrman Shahar, Naama Orenstein, Lina Basel Salmon, Barbara Oehl-Jaschkowitz, Erin Torti, Sureni V Mullegama, Shaun A Hussain, Paulina Mabe, Carolina Mendoza Fuentes, Francis Ramond, Víctor Faundes, Peter D Turnpenny, Dennis Witt, Miriam Bertrand, Ute Grasshoff, Allan Bayat, Marine Lebrun, Rebecca L Poole, David FitzPatrick, Renzo Guerrini, Annalisa Vetro, Oded Wechsberg, Mona Grimmel, Caroline Dalgliesh

Journal: Genetics in medicine : official journal of the American College of Medical Genetics 2023;25(4):100003

PMID: 36549593

Free Full Text on Elsevier Science View on PubMed

Abstract

PURPOSE

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.

METHODS

A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing 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.

RESULTS

All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform. All 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, whereas 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.

CONCLUSION

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.

Address: Service de Génétique, Hôpital Nord, CHU Saint-Etienne, Saint-Etienne, France. Electronic address: [email protected].; Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany.; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Maccabi Healthcare Services, Tel Aviv, Israel.; Neuroscience Department, Meyer Children's Hospital and University of Florence, Florence, Italy.; MRC Human Genetics Unit, The University of Edinburgh, Edinburgh, Scotland, United Kingdom.; NHS Education for Scotland South East Region, South East of Scotland Clinical Genetics Service, Edinburgh, United Kingdom.; Service de Génétique, Hôpital Nord, CHU Saint-Etienne, Saint-Etienne, France.; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark; Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Center, Dianalund, Denmark.; Clinical Genetics, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom.; Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Santiago, Chile.; Unidad de Endocrinología, División de Pediatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.; Unidad de Neurología, Hospital de Niños Dr. Exequiel González Cortés, Santiago, Chile.; Division of Pediatric Neurology, University of California, Los Angeles, Los Angeles, CA.; Clinical Genomics Program, GeneDx, MD.; Practice of Human Genetics, Homburg (Saar), Germany.; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; Pediatric Immunogenetics, Felsenstein Medical Research Center, Petach Tikva, Israel.; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.; Abteilung für Humangenetik, Ruhr-Universitat Bochum, Bochum, Germany.; Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL.; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany.; Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: [email protected].

DOI: 10.1016/j.gim.2022.100003