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A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.
European Journal of Human Genetics ( IF 5.2 ) Pub Date : 2020-09-08 , DOI: 10.1038/s41431-020-00717-5
Shereen G Ghosh 1, 2 , Marcello Scala 3, 4 , Christian Beetz 5 , Guy Helman 6, 7 , Valentina Stanley 1, 2 , Xiaoxu Yang 1, 2 , Martin W Breuss 1, 2 , Neda Mazaheri 8 , Laila Selim 9 , Fatemeh Hadipour 10 , Lynn Pais 11 , Chloe A Stutterd 6, 7, 12 , Vasiliki Karageorgou 5 , Amber Begtrup 13 , Amy Crunk 13 , Jane Juusola 13 , Rebecca Willaert 13 , Leigh A Flore 14 , Kelly Kennelly 14 , Christopher Spencer 15 , Martha Brown 15 , Pamela Trapane 15 , Anna C E Hurst 16 , S Lane Rutledge 16 , Dana H Goodloe 16 , Marie T McDonald 17 , Vandana Shashi 17 , Kelly Schoch 17 , , Hoda Tomoum 18 , Raghda Zaitoun 18 , Zahra Hadipour 10 , Hamid Galehdari 8 , Alistair T Pagnamenta 19 , Majid Mojarrad 20, 21, 22 , Alireza Sedaghat 23 , Patrícia Dias 24 , Sofia Quintas 25 , Atiyeh Eslahi 20, 26 , Gholamreza Shariati 27 , Peter Bauer 5 , Cas Simons 6, 7 , Henry Houlden 4 , Mahmoud Y Issa 28 , Maha S Zaki 28 , Reza Maroofian 4 , Joseph G Gleeson 1, 2
Affiliation  

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.



中文翻译:

一种相对常见的纯合 TRAPPC4 剪接变体与早期婴儿神经退行性综合征有关。

运输蛋白颗粒 (TRAPP) 复合物,包括 TRAPPC4 蛋白,在称为囊泡束缚的过程中调节脂质细胞器之间的膜运输。由于共享的 c.454+3A>G 剪接变体, TRAPPC4最近与四个不相关家族的隐性神经发育状况有关。在这里,我们报告了来自 17 个独立家庭的 23 名患有早发性神经退行性疾病的患者,我们还发现了 TRAPPC4 中的纯合变异 hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G )通过外显子组或基因组测序。在超过 10,000 名患有神经发育疾病的患者中,没有发现其他临床相关的 TRAPPC4变体。我们发现载波频率为TRAPPC4 c.454+3A>G 为每 10,000 名健康个体 2.4–5.4。具有纯合TRAPPC4 c.454+3A>G 变异的受影响个体表现出严重的精神运动延迟、发育退化、早发性癫痫、小头畸形和进行性痉挛性四肢瘫痪。基于 RNA 测序,由于使用了下游隐蔽的剪接供体位点,该变体导致部分外显子 3 跳跃和异常转录物的产生,预测了过早的终止密码子和无义介导的衰变。这些数据证实了TRAPPC4 c.454+3A>G 变异的致病性,并细化了TRAPPC4相关脑病的临床表现。

更新日期:2020-09-08
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