Intellectual disability - microarray and sequencing
Gene: TRAPPC6BComment on list classification: Updated rating from Amber to Green based on Aug 2019 review by Konstantinos Varvagiannis. Konstantinos notes an additional 2019 paper (Nair et al) who report a Lebanese patient with global DD and ID, who is homozygous for a nonsense variant in TRAPPC6B (p.Leu8*). The unaffected mother was a heterozygous carrier. In contrast to previous cases, the patient did not show any seizures, but the authors note he was only 3.5 years old at the time of writing, and will be monitored for seizure events. ID/DD is a consistent phenotype across cases. This takes the number of cases to 3 (with the 3 families in Marin-Valencia forming 1 case), with 3 separate variants. Therefore Green rating is appropriate.Created: 24 Oct 2019, 4:27 p.m. | Last Modified: 24 Oct 2019, 4:27 p.m.
Panel Version: 2.1087
9 individuals from 5 families have been reported, all harboring loss-of-function variants in homozygous state.
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Marin-Valencia et al. (2018 - PMID: 28626029) describe 6 individuals from 3 consanguineous families - all from Egypt - homozygous for a specific splicing variant. Features incl. global DD and ID (6/6), seizures (6/6 - GTC), microcephaly. Some presented with extrapyramidal symptoms. TRAPPC6B is expressed in the fetal brain and the adult brain and spinal cord. The splicing variant affected the splice-donor site in both protein coding transcripts [NM_001079537.2 (the predominant transcript) and NM_177452.3 | in both : c.150-2A>G) and skipping of exon 2 was shown upon RT-PCR in patient fibroblasts.
The variant - probably a founder mutation - has an AF of 0.00004991 in gnomAD (possibly 0.0023 in Egyptians) and was found following WES, with a linkage peak with a MPT pLOD score > 2 in 2 families.
The transport protein particle (TRAPP) is a multisubunit protein complex regulating mebrane trafficking from the ER to the Golgi and plasma membrane. The different TRAPP complexes (I,II,III) comprise different subunits apart from the 7 core ones.
Patient fibroblasts did not show obvious differences in the ER/Golgi morphology or defects in trafficking.
Mutations in genes for other subunits cause disorders with neurological manifestations and/or - in the case of TRAPPC9 - intellectual disability.
Zebrafish studies were carried out. In zebrafish trappc6b transcript is detected in the CNS early (24 hpf). Morpholino knockdown led to decreased survival, reduced head size despite normal body length (similar the microcephaly phenotype) with increase in apoptotic cells (which might be compatible with the course in few individuals) and neuronal hyperexcitability with lowered seizure threshold (seizures reported in 6/6 patients).
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Harripaul et al. (2018 - PMID: 28397838) identified 2 individuals from a consanguineous family (from cohort of 192 consanguineous families with ID from Pakistan/Iran investigated by WES). Similarly to the previous report, both subjects were homozygous for a LoF variant (NM_177452.4:c.124C>T or p.Arg42Ter). Sanger confirmation and segregation studies were carried out. The authors do not provide additional information or functional evidence.
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Nair et al. (2019 - DOI: 10.1055/s-0039-1693664) report on a boy born to consanguineous Lebanese parents, homozygous for a stopgain variant (NM_001079537.2:c.23T>A or p.Leu8*). Features included DD and ID, microcephaly, MRI findings of thin corpus callosum and periventricular leucomalacia (thin corpus callosum was also reported in the first study with cortical/cerebellar atrophy in some). The mother was heterozygous for the variant.
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Biallelic TRAPPC6B mutations cause Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy (MIM 617862) with severe ID among the clinical features.
TRAPPC6B is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboudumc, Victorian Clinical Genetics, Utrecht UMC, GeneDx etc). The gene is not associated with any phenotype in G2P.
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As a result this gene could possibly be considered for upgrade to green (5 families although in 3 due to a founder mutation, biallelic LoF in all affected individuals, RNA studies for the splicing variant, some suggestive features in zebrafish model, neurological manifestations/ID as part of other TRAPP complex related disorders) or remain amber pending further evidence (clinical details, defect at the cell level).Created: 25 Aug 2019, 7:36 p.m. | Last Modified: 25 Aug 2019, 7:36 p.m.
Panel Version: 2.1015
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Rated gene as Amber based on current information in the literature and external expert reviewCreated: 17 Jul 2018, 11:01 a.m.
Added new gene from expert review. Marin-Valencia et al. (2018) PMID: 28626029 found homozygous splice mutations in TRAPPC6B (NM_177452.3(TRAPPC6B):c.150-2A>G) who reported in six individuals from three unrelated families with a neurodevelopmental disorder with microcephaly, epilepsy and autistic features, a truncating loss of function mutation in this gene is associated with ID. The variant segregated with the disorder in the families. Harripaul et al. (2018) PMID:28397838 described a further 2 patients from a consanguineous family (IDH3) with intellectual disability and identified a homozygous truncating mutation in the TRAPPC6B gene (NM_177452.3 (TRAPPC6B):c.124C>T). Confirmed by Sanger sequencing and segregated with the disorder in the family. Clinical information, functional studies of the variant, and studies of patient cells were not reported or performed. However, the patients were ascertained from a cohort of 192 consanguineous families from Pakistan and Iran with autosomal recessive intellectual disability, which this panel representsCreated: 17 Jul 2018, 11 a.m.
Comment on phenotypes: added OMIM MIMidCreated: 17 Jul 2018, 9:41 a.m.
Multiple individuals from 4 families reported in the literature with bi-allelic variants; however, some may be related by descent. Consider inclusion as Amber.Created: 22 Jun 2018, 2:59 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy
Publications
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Publications for gene: TRAPPC6B were set to 28626029; 28397838
Gene: trappc6b has been classified as Green List (High Evidence).
Source Victorian Clinical Genetics Services was added to TRAPPC6B.
Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: TRAPPC6B were set to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862
Publications for gene: TRAPPC6B were set to 28626029; 28397838
TRAPPC6B was added to Intellectual disability panel. Sources: Literature
TRAPPC6B was created by Zornitza Stark