Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

Töpf, AnaPyle, AngelaGriffin, HelenMatalonga, LeslieSchon, KatherineSolve-RD SNV-indel working groupSolve-RD DITF-euroNMDSickmann, AlbertSchara-Schmidt, UlrikeHentschel, AndreasChinnery, Patrick F.Kölbel, HeikeRoos, Andreas2021-11-192021-11-192021Töpf A, Pyle A, Griffin H, Matalonga L, Schon K; Solve-RD SNV-indel working group; Solve-RD DITF-euroNMD, Sickmann A, Schara-Schmidt U, Hentschel A, Chinnery PF, Kölbel H, Roos A, Horvath R. Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1). Eur J Hum Genet. 2021;29(9):1348-53. DOI: 10.1038/s41431-021-00851-81018-4813http://hdl.handle.net/10230/49021TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient's fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism.application/pdfeng© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41431-021-00851-8Genetics researchNext-generation sequencinginfo:eu-repo/semantics/openAccess