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

Abstract

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.

The RD‐Connect Genome‐Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases

“…To this end, 19,000 genome‐phenome datasets are in the process of being collected, processed, and analyzed in the RD‐Connect GPAP. Programmatic reanalysis of the first ~4,000 families resulted in rapid resolution of 120 families (de Boer et al, 2021; Matalonga et al, 2021; Schüle et al, 2021; te Paske et al, 2021; Topf et al, 2021). These numbers, which have increased substantially since publication, were achieved through the identification of causative variants that had either been missed by the original variant filtering strategies undertaken by submitting centers, or were dismissed as being unimportant at the time due to a lack of supporting evidence, but for which further information has come to light linking the gene to the phenotype of the case in the intervening period.…”

Remote visualization of large-scale genomic alignments for collaborative clinical research and diagnosis of rare diseases

“…Preliminary (re-)analysis of the first 4,400 Solve-RD cases resulted in 255 new diagnoses in mid-2021. 15 , 18 Figure 2 and Video S1 illustrate an example of the visualization of genomic alignments for a causative homozygous variant in TRIP4 in a patient with cerebellar hypoplasia and spinal muscular atrophy. 18

Figure 2 Visualization of slices of genomic alignments archived at the EGA A screenshot of the GPAP’s embedded IGV displaying a slice of a BAM file, archived at the EGA, from a patient with cerebellar hypoplasia and spinal muscular atrophy.

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“… 15 , 18 Figure 2 and Video S1 illustrate an example of the visualization of genomic alignments for a causative homozygous variant in TRIP4 in a patient with cerebellar hypoplasia and spinal muscular atrophy. 18

Figure 2 Visualization of slices of genomic alignments archived at the EGA A screenshot of the GPAP’s embedded IGV displaying a slice of a BAM file, archived at the EGA, from a patient with cerebellar hypoplasia and spinal muscular atrophy. The genomic data show a homozygous single-nucleotide change at position 15:64698591C>T (NM_016213.5:c.760C>T [pArg254Ter]).

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“…The overall implementation currently enables RD-Connect users to remotely access and visualize 11,750 datasets from patients and relatives submitted through the Solve-RD project, which has identified causative variants in hundreds of cases with an RD. 5 , 14 , 15 , 16 , 17 , 18 …”

‘A novel TRIP4 Variant Associated with Peripheral Neuropathy: Expanding the Clinical and Genetic Spectrum of ASC1-Related Myopathy’

“…ASC-1 complex was proposed to play a relevant role in congenital and degenerative motorneuron disease, representing a link between SMA and amyotrophic lateral sclerosis [ 9 ]. One patient had cerebellar hypoplasia in addition to “SMA-like” phenotype and congenital bone fractures [ 10 ]. We did not observe any signs of first motor neuron involvement nor central nervous system malformations in our two siblings, but growing evidence supports strong association of TRIP4 defects with neuronal involvement [ 4, 9, 10 ].…”