A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome


Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4–5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

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Fig. 1: Pedigrees, chromatogram, TRAPPC4 gene and protein, and mRNA analysis.
Fig. 2: Clinical and radiological characterization of TRAPPC4 patients.

Data availability

The identified TRAPPC4 variant was submitted to the LOVD database at https://databases.lovd.nl (Individual ID #00306235, https://databases.lovd.nl/shared/individuals/00306235; genomic variant ID #0000673996, https://databases.lovd.nl/shared/variants/0000673996). The accession number for this variant in ClinVar is VCV000812649.1. The accession numbers in dbGAP are phs001272 and phs000744.


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The authors thank the patients and their families for participation in this study. We would like to thank Grazia Mancini for communicating unpublished results. The authors acknowledge Baylor Genetics Laboratories for supplying data. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number(s) U01HG007672 (PI- Shashi V, Duke University). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Drs. Jennifer Friedman and Dillon Chen for providing comments on the manuscript.


This work was supported by NIH grants R01NS098004, R01NS048453, and R01NS106387, SFARI research award to J.G.G. S.G. was sponsored by the Ruth L. Kirschstein Institutional National Research Service Award (T32 GM008666) from the National Institute on Deafness and Other Communication Disorders and by award F31HD095602 from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), and the Yale Center for Mendelian Genomics (Yale CMG, UM1HG006504) and supported by NHGRI, NEI, and NHLBI grant UM1 HG008900 and NHGRI R01 HG009141, the MRC (MR/S01165X/1, MR/S005021/1, G0601943), the NIH Research UCL Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), the Victorian Government’s Operational Infrastructure Support Program, and by the Australian Medical Research Future Fund project, “Massimo’s Mission”.

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Correspondence to Reza Maroofian or Joseph G. Gleeson.

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A.B., A.C., J.J., and R.W. are employees of GeneDx, Inc. All other authors declare no conflict of interest.

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Ghosh, S.G., Scala, M., Beetz, C. et al. A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-00717-5

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