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Comment
. 2020 Oct 1;143(10):e83.
doi: 10.1093/brain/awaa256.

Biallelic in-frame deletion in TRAPPC4 in a family with developmental delay and cerebellar atrophy

Ahmed K Saad  1   2 , Dana Marafi  1   3 , Tadahiro Mitani  1 , Angad Jolly  1   4 , Haowei Du  1 , Hasnaa M Elbendary  5 , Shalini N Jhangiani  6 , Zeynep C Akdemir  1 ; Baylor-Hopkins Center for Mendelian Genomics; Richard A Gibbs  1   6 , Jill V Hunter  7   8 , Claudia M B C Carvalho  1 , Davut Pehlivan  1   9   10 , Jennifer E Posey  1 , Maha S Zaki  5 , James R Lupski  1   6   9   11
Affiliations
Comment

Biallelic in-frame deletion in TRAPPC4 in a family with developmental delay and cerebellar atrophy

Ahmed K Saad et al. Brain. .
No abstract available

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Figures

Figure 1
Figure 1
Family pedigree with genetic findings and MRI images of patients. (A) Pedigree of the family. Proband is identified with a black arrow. Affected individuals are shaded black. Identifier and genotype are included below each individual. [B(1)] Patient BAB13325 at 7 years of age. [B(2–4)] Brain MRI images of Patient BAB13325 at 2 years of age. [B(2)] T2 sequence (sagittal view) showing thinning of the body of corpus callosum, moderate atrophy of the cerebellar vermis, and giant cysterna magna, a nonspecific finding reflective of the vermian hypoplasia. [B(3)] T2 sequence (axial view) showing normal cerebrum with no evidence of atrophy. Note that volume of cerebrum is preserved in contrast to severe atrophy in subjects with the splice variant (Van Bergen et al., 2020). [B(4)] T2 sequence (axial view) showing T2 hyperintensity at the bilateral posterior centrum semiovale. Although myelination is not complete at this age, the presence of simile signal abnormality in the Brain MRI of the sibling (Patient BAB13328) at 3 years of age suggests an abnormality in myelination. [C(1)] A picture of Patient BAB13328 at 3 years of age. [C(2–4)] Brain MRI images of Patient BAB13328 at 3 years of age. [C(2)] T2 sequence (sagittal view) showing mild thinning of the body of corpus callosum, moderate atrophy of the vermis, and giant cisterna magna with a retrocerebellar cyst. [C(3)] T2 sequence (axial view) showing generous sylvian fissures and prominent sulci suggestive of mild cerebral atrophy. [C(4)] T2 sequence (axial view) showing T2 signal hyperintensity at the bilateral posterior centrum semiovale consistent with abnormal myelination and often seen in association with motor developmental delay. (D) PCR analysis. The gel electrophoresis of the amplified short DNA fragment harbouring variant position showed one PCR product corresponding to the expected size (127 bp) from the allele harbouring the deletion in all family members, whereas one additional PCR product (154 bp) representing the wild-type allele was observed in the parents and the unaffected sister. (E) Sanger sequencing results showing autosomal recessive Mendelian segregation of the variant (c.638_*4del) among family members. Heterozygous individuals have peak on peak appearance. Microhomology is highlighted in yellow.
Figure 2
Figure 2
Variant schematic representation, AOH plot, and protein structure prediction. (A) Schematic structure of TRAPPC4 (NM_016146.6). Green circles show the location of the variants. The splice site variant (c.453+3A>G) leads to an alternative splicing that results in skipping of exon 3. Exon 3 skipping causes a frameshift, produces a premature termination codon, and results in nonsense-mediated decay (Van Bergen et al., 2020). The second variant, an in-frame 27 bp deletion, is the one identified in this study (green circle). The deletion variant is located in the last exon and involves the canonical stop codon (highlighted in red). The deletion variant is predicted to result in stop-loss, further extension of the coding sequence and generation of an elongated protein. Our proposed pathway is highlighted in the yellow box. (B) Plot for regions of absence of heterozygosity (AOH), which is marked by grey zones, on chromosome 11 in Patients BAB13325 and BAB13328. Note that the variant in TRAPPC4 is located within a shared AOH region of 2.1 Mb. (C) Protein 3D structure prediction showing the C-terminal part of TRAPPC4 protein. Left: The wild-type structure has two helical structures (in blue) whereas the mutated protein (right), has an intercalated helix (in red). In silico prediction was performed using the publicly available tools: ROBETTA server, Protein Structure Prediction Center fully automated servers (Kim et al., 2004). Protein visualization and labelling was done using Pymol software.
See this image and copyright information in PMC

Comment in

Comment on

  • Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.
    Van Bergen NJ, Guo Y, Al-Deri N, Lipatova Z, Stanga D, Zhao S, Murtazina R, Gyurkovska V, Pehlivan D, Mitani T, Gezdirici A, Antony J, Collins F, Willis MJH, Coban Akdemir ZH, Liu P, Punetha J, Hunter JV, Jhangiani SN, Fatih JM, Rosenfeld JA, Posey JE, Gibbs RA, Karaca E, Massey S, Ranasinghe TG, Sleiman P, Troedson C, Lupski JR, Sacher M, Segev N, Hakonarson H, Christodoulou J. Van Bergen NJ, et al. Brain. 2020 Jan 1;143(1):112-130. doi: 10.1093/brain/awz374. Brain. 2020. PMID: 31794024 Free PMC article.

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