TY - JOUR
T1 - A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome
AU - Undiagnosed Diseases Network
AU - Ghosh, Shereen G.
AU - Scala, Marcello
AU - Beetz, Christian
AU - Helman, Guy
AU - Stanley, Valentina
AU - Yang, Xiaoxu
AU - Breuss, Martin W.
AU - Mazaheri, Neda
AU - Selim, Laila
AU - Hadipour, Fatemeh
AU - Pais, Lynn
AU - Stutterd, Chloe A.
AU - Karageorgou, Vasiliki
AU - Begtrup, Amber
AU - Crunk, Amy
AU - Juusola, Jane
AU - Willaert, Rebecca
AU - Flore, Leigh A.
AU - Kennelly, Kelly
AU - Spencer, Christopher
AU - Brown, Martha
AU - Trapane, Pamela
AU - Hurst, Anna C.E.
AU - Lane Rutledge, S.
AU - Goodloe, Dana H.
AU - McDonald, Marie T.
AU - Shashi, Vandana
AU - Schoch, Kelly
AU - Tomoum, Hoda
AU - Zaitoun, Raghda
AU - Hadipour, Zahra
AU - Galehdari, Hamid
AU - Pagnamenta, Alistair T.
AU - Mojarrad, Majid
AU - Sedaghat, Alireza
AU - Dias, Patrícia
AU - Quintas, Sofia
AU - Eslahi, Atiyeh
AU - Shariati, Gholamreza
AU - Bauer, Peter
AU - Simons, Cas
AU - Houlden, Henry
AU - Issa, Mahmoud Y.
AU - Zaki, Maha S.
AU - Maroofian, Reza
AU - Gleeson, Joseph G.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to European Society of Human Genetics.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85090433089&partnerID=8YFLogxK
U2 - 10.1038/s41431-020-00717-5
DO - 10.1038/s41431-020-00717-5
M3 - Article
C2 - 32901138
AN - SCOPUS:85090433089
SN - 1018-4813
VL - 29
SP - 271
EP - 279
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 2
ER -