Intellectual disability - microarray and sequencing
Gene: TRAPPC10
Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.
The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.Created: 12 Apr 2023, 9:05 a.m. | Last Modified: 12 Apr 2023, 9:05 a.m.
Panel Version: 5.30
Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.
The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.Created: 12 Apr 2023, 9:04 a.m. | Last Modified: 12 Apr 2023, 9:04 a.m.
Panel Version: 5.30
Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.
The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.Created: 12 Apr 2023, 9:04 a.m. | Last Modified: 12 Apr 2023, 9:04 a.m.
Panel Version: 5.30
Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.
The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.Created: 12 Apr 2023, 9:04 a.m. | Last Modified: 12 Apr 2023, 9:04 a.m.
Panel Version: 5.30
Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.
The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.Created: 12 Apr 2023, 9:03 a.m. | Last Modified: 12 Apr 2023, 9:03 a.m.
Panel Version: 5.30
Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.
The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.Created: 12 Apr 2023, 9:03 a.m. | Last Modified: 12 Apr 2023, 9:03 a.m.
Panel Version: 5.29
Comment on list classification: This gene should be rated AMBER as there are only two unrelated cases with intellectual disability and global developmental delay. Although there are functional studies available, no cognitive defects were reported in the mouse model.
The 'watchlist' tag has been added to review this gene rating regularly in light of any new evidence.Created: 12 Apr 2023, 9:03 a.m. | Last Modified: 12 Apr 2023, 9:03 a.m.
Panel Version: 5.29
As reviewed by Konstantinos Varvagiannis, there are two unrelated consanguineous Pakistani families with homozygous variants in TRAPPC10 reported with a neurodevelopmental disorder characterised by microcephaly, short stature, severe intellectual disability, global developmental delay, speech impairment and behavioural abnormalities. All ten individuals from both families presented with severe intellectual disability and global developmental delay.
PMID:35298461 also reported neuroanatomical brain defects and microcephaly in null mouse model and other functional studies in transfected cell lines.
This gene has been associated with relevant phenotypes in both OMIM (MIM #620027) and Gene2Phenotype (with 'limited' rating).Created: 12 Apr 2023, 8:48 a.m. | Last Modified: 12 Apr 2023, 8:48 a.m.
Panel Version: 5.25
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Publications
Please consider upgrade to amber rating (2 families/variants, highly similar features to other TRAPPopathies, extensive studies for the effect of variants and the role of TRAPPC10, mouse model). Consider also inclusion in other relevant panels (e.g. microcephaly).
--------
Rawlins et al (2022 - PMID: 35298461) identify biallelic TRAPPC10 variants in 10 individuals with a severe microcephalic neurodevelopmental disorder belonging to 2 consanguineous families from Pakistan. The second family was previously reported within a cohort of 22 consanguineous families studied to identify novel candidate genes for NDD (MR107 in PMID: 30167849).
Overlapping features included hypotonia (8/8 - 1 fam), global DD (10/10), severe intellectual disability (10/10), microcephaly (9/10 - OFC ranged from -1.32 to -7.46 SDs, likely postnatal), short stature (8/10 below - 2 SDs, range -1.78 to -5.29) and behavioral abnormalities (10/10). Waddling gait and seizures were each observed in 3 subjects (from 1 family).
In the 1st multi-nuclear family, SNP-genotyping was performed in 3/8 affected members with exome sequencing in 1 of these 3. There was a single homozygous region above 1 Mb shared by all three (3.5 Mb - chr21:47179611-46678912 in hg38). A TRAPPC10 frameshift variant (NM_003274.4:c.3392del / p.(Gly1131Valfs*19) was the single candidate within this region, lying in the second last (22/23) exon and predicted to result in NMD.
Segregation was compatible in all 8/8 affected subjects, 6/6 unaffected sibs (htz or hmz for wt) and 3 carrier parent pairs. The variant is not present in gnomAD. rtPCR in RNA from the blood of an affected individual confirmed that the variant results in a premature stop codon. Further studies for this variant below.
In the 2nd family (details from PMID: 30167849) genome-wide genotyping was performed and data were analyzed using hmz mapping and parametric multipoint linkage analysis (AR, compl. penetrance, no phenocopies, AF:0.001). Exome sequencing was performed for 1 affected individual. Within a 21q22.2-q22.3 region with LOD score (θ=0) of 2.06, the following TRAPPC10 variant was identified NM_003274.4:c.2786C>T/p.(Pro929Leu), absent from gnomAD with several in silico predictions in favour of a deleterious effect (e.g. CADD:35). This co-segregated with the ID phenotype using Sanger seq in DNA samples from all available family members (2 affected sibs hmz / parents and 2 unaffected sibs were all htz). Further studies for this variant discussed below.
As the authors discuss, the transport protein particles (TRAPPs) are multiprotein complexes. Three TRAPP complexes (TRAPPI, II, III) have been described in yeast, having important roles in secretory and endocytic subcellular trafficking pathways. In humans there are only 2 TRAPP complexes, namely TRAPPII & III, sharing their conserved subunits with two additional subunits specific to TRAPPII (TRAPPC9 and 10) and four for TRAPPIII (TRAPPC8/11/12/13).
Mutations in 10 genes encoding different TRAPP subunits of the TRAPP II and III complexes have been associated with a spectrum of human disorders ("TRAPPopathies"), commonly neurodevelopmental. This applies to TRAPPC2L/4/6A/6B/9/11/12/14.
TRAPPII has been reported to have diverse cellular roles incl. Golgi, coat protein complex vesicular, lipid droplet, centrosomal and ciliary functions (several Refs provided). The complex has a guanine nucleotide exhange factor activity.
Biallelic pathogenic variants in TRAPPC9, coding for a TRAPPII-specific subunit (as also the case for TRAPPC10), cause Mental retardation, autosomal recessive 13 (# 613192) with DD, ID and postnatal microcephaly among the core features.
In TRAPPII, TRAPPC10 interacts with TRAPPC2L. Studies in yeast cells demonstrated that Gly1131Valfs*19 and Pro929Leu are expressed but exhibited reduced interaction with TRAPPC2L.
In a patient derived lymphoblast cell line (Gly1131Valfs*19), core TRAPP protein levels (TRAPPC2L, C2, C3) were slightly reduced. TRAPPC10 was not detected, as the antibody employed was directed to a more downstream region of the protein. Full length TRAPPC9 was absent. TRAPPIII-specific protein levels were unaffected.
LCL cells from a control and the aforementioned individual were lysed and probed for TRAPP proteins, showing absence of both TRAPPC10 and 9 in patient but not in control cells. There was no change detected for core proteins (2/2L/3), nor for TRAPIII proteins.
As above, generation of HEK293 TRAPPC10-ko cell lines, confirmed slight reduction in core TRAPP proteins, no effect for TRAPPIII-specific ones and absence of TRAPPC9. TRAPPC10-/- cells exhibited a trafficking defect (arrival, trafficking delay and release from Golgi) for a marker protein, not observed in control cells. This was rescued upon transfection with WT TRAPPC10, but only to a lesser extent for Gly1131Valfs*19 and Pro929Leu.
Constructs for wt TRAPPC10 and each of the variants were transfected in HEK293 cells. In lysates (over 4 days), protein levels for the variants dropped more significantly compared to WT, with this decrease blocked after inclusion of a proteasome inhibitor, suggesting enhanced degradation for mutant proteins.
Transfection of wt TRAPPC10 into TRAPPC10-/- HEK293 cells restored TRAPPC9 levels, observed to a much lesser extent upon overexpression of the missense and frameshift variant.
Trappc10-/- mouse model with comparison of neuroanatomical defects with wt mice, suggested significant reduction in size of several neuroanatomical parameters and total brain area (recapitulating microcephaly). The reduction in size was limited to white matter structures. Myelination of ant.commissure and internal capsule was also reduced. The short stature human phenotype was not reproduced in mice, as overall body length was unaffected despite marginal reduction in long bone length.
Comparison of homozygous mutant Trappc10 mice with Trappc9 ones, suggested that the impact of Trappc10 loss was more severe and some neuroanatomical phenotypes more specific to Trappc10.
--------
There is no associated phenotype in OMIM or PanelApp Australia, nor any relevant GenCC entry. SysID lists TRAPPC10 among the candidate ID genes (cited PMID: 30167849). G2P includes TRAPPC10 in it's DD panel ("TRAPPC10-associated intellectual disability", confidence category: limited, cited PMID: 30167849).Created: 25 Mar 2022, 10:59 a.m. | Last Modified: 25 Mar 2022, 10:59 a.m.
Panel Version: 3.1523
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Short stature; Gait disturbance
Publications
Comment on list classification: New gene added by Aleš Maver (Clinical Institute of Medical Genetics). This gene is not associated with a phenotype in OMIM, but is possibly associated with a disease in Gene2Phenotype. The affected individuals in PMID:30167849 (2 individuals from the same family) had severe ID. As I do not have access to the ESHG2021 talk, this gene has been given a Red rating until further evidence is available.Created: 13 Sep 2021, 3:31 p.m. | Last Modified: 13 Sep 2021, 3:31 p.m.
Panel Version: 2.223
This gene was originally reported in association with microcephalic NDD in PMID:30167849 (biallelic missense variant) and was replicated in a large family consanguineous family with a biallelic frameshift variant - reported at the ESHG2021 conference, talk C16.4 by Rawlins).
Sources: OtherCreated: 30 Aug 2021, 9:01 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Gene: trappc10 has been classified as Amber List (Moderate Evidence).
Gene: trappc10 has been classified as Amber List (Moderate Evidence).
Gene: trappc10 has been classified as Amber List (Moderate Evidence).
Gene: trappc10 has been classified as Amber List (Moderate Evidence).
Gene: trappc10 has been classified as Amber List (Moderate Evidence).
Gene: trappc10 has been classified as Amber List (Moderate Evidence).
Gene: trappc10 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Tag watchlist tag was added to gene: TRAPPC10.
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Phenotypes for gene: TRAPPC10 were changed from Intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849; 35298461
Publications for gene: TRAPPC10 were set to 30167849
Phenotypes for gene: TRAPPC10 were changed from microcephaly (disease), MONDO:0001149 to Intellectual disability, MONDO:0001071
gene: TRAPPC10 was added gene: TRAPPC10 was added to Intellectual disability. Sources: Expert Review Red,Other Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAPPC10 were set to 30167849 Phenotypes for gene: TRAPPC10 were set to microcephaly (disease), MONDO:0001149 Penetrance for gene: TRAPPC10 were set to Complete