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

Publication ,  Journal Article
Ghosh, SG; Scala, M; Beetz, C; Helman, G; Stanley, V; Yang, X; Breuss, MW; Mazaheri, N; Selim, L; Hadipour, F; Pais, L; Stutterd, CA; Dias, P ...
Published in: Eur J Hum Genet
February 2021

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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Published In

Eur J Hum Genet

DOI

EISSN

1476-5438

Publication Date

February 2021

Volume

29

Issue

2

Start / End Page

271 / 279

Location

England

Related Subject Headings

  • Vesicular Transport Proteins
  • Syndrome
  • RNA Splicing
  • RNA Splice Sites
  • Pedigree
  • Neurodevelopmental Disorders
  • Nerve Tissue Proteins
  • Microcephaly
  • Male
  • Humans
 

Citation

APA
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Ghosh, S. G., Scala, M., Beetz, C., Helman, G., Stanley, V., Yang, X., … Gleeson, J. G. (2021). A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome. Eur J Hum Genet, 29(2), 271–279. https://doi.org/10.1038/s41431-020-00717-5
Ghosh, Shereen G., Marcello Scala, Christian Beetz, Guy Helman, Valentina Stanley, Xiaoxu Yang, Martin W. Breuss, et al. “A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.Eur J Hum Genet 29, no. 2 (February 2021): 271–79. https://doi.org/10.1038/s41431-020-00717-5.
Ghosh SG, Scala M, Beetz C, Helman G, Stanley V, Yang X, et al. A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome. Eur J Hum Genet. 2021 Feb;29(2):271–9.
Ghosh, Shereen G., et al. “A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.Eur J Hum Genet, vol. 29, no. 2, Feb. 2021, pp. 271–79. Pubmed, doi:10.1038/s41431-020-00717-5.
Ghosh SG, Scala M, Beetz C, Helman G, Stanley V, Yang X, Breuss MW, Mazaheri N, Selim L, Hadipour F, Pais L, Stutterd CA, Karageorgou V, Begtrup A, Crunk A, Juusola J, Willaert R, Flore LA, Kennelly K, Spencer C, Brown M, Trapane P, Hurst ACE, Lane Rutledge S, Goodloe DH, McDonald MT, Shashi V, Schoch K, Undiagnosed Diseases Network, Tomoum H, Zaitoun R, Hadipour Z, Galehdari H, Pagnamenta AT, Mojarrad M, Sedaghat A, Dias P, Quintas S, Eslahi A, Shariati G, Bauer P, Simons C, Houlden H, Issa MY, Zaki MS, Maroofian R, Gleeson JG. A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome. Eur J Hum Genet. 2021 Feb;29(2):271–279.

Published In

Eur J Hum Genet

DOI

EISSN

1476-5438

Publication Date

February 2021

Volume

29

Issue

2

Start / End Page

271 / 279

Location

England

Related Subject Headings

  • Vesicular Transport Proteins
  • Syndrome
  • RNA Splicing
  • RNA Splice Sites
  • Pedigree
  • Neurodevelopmental Disorders
  • Nerve Tissue Proteins
  • Microcephaly
  • Male
  • Humans