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

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Töpf, Ana 
Pyle, Angela 
Griffin, Helen 
Matalonga, Leslie 

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.

Cerebellum, Developmental Disabilities, Exome, Genetic Testing, Humans, Infant, Male, Muscular Atrophy, Spinal, Nervous System Malformations, Proteome, Transcription Factors
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Eur J Hum Genet
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Springer Science and Business Media LLC
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Medical Research Council (MR/N025431/2)
MRC (MR/N027302/2)
Addenbrooke's Charitable Trust (ACT) (64/17 A)
Wellcome Trust (109915/A/15/Z)
Wellcome Trust (212219/Z/18/Z)
Wellcome Trust (109915_A_15_Z)
MRC (MR/V009346/1)
National Institute for Health and Care Research (IS-BRC-1215-20014)