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

Lookup NU author(s): Dr Ana TopfORCiD, Dr Angela Pyle, Dr Helen GriffinORCiD, Professor Patrick Chinnery, Dr Andreas Roos, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021. The Author(s).TRIP4 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.

Publication metadata

Author(s): Topf A, Pyle A, Griffin H, Matalonga L, Schon K, Sickmann A, Schara-Schmidt U, Hentschel A, Chinnery PF, Kolbel H, Roos A, Horvath R

Publication type: Article

Publication status: Published

Journal: European Journal of Human Genetics

Year: 2021

Volume: 29

Issue: 9

Pages: 1348-1353

Print publication date: 01/09/2021

Online publication date: 01/06/2021

Acceptance date: 26/02/2021

Date deposited: 01/06/2022

ISSN (print): 1018-4813

ISSN (electronic): 1476-5438

Publisher: Springer Nature


DOI: 10.1038/s41431-021-00851-8

PubMed id: 34075209


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Funder referenceFunder name
109915/Z/15/ZWellcome Trust
779257European Commission
MR/N025431/1Medical Research Council (MRC)
MR/N027302/1Medical Research Council (MRC)
MR/S005021/1Medical Research Council (MRC)
The Lily Foundation
The Evelyn Trust