Genetic Epilepsy
Gene: TRAPPC12 Green List (high evidence)I don't know
Update - 3 unrelated families with characteristic phenotype involving microcephaly and epilepsy (Milev et al 2017, Aslanger et al 2020). 4th case from unrelated family with novel homozygous missense variants reported with no microcephaly or clinically apparent epilepsy (Aslanger et al 2020).
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3 individuals from 2 unrelated families reported by Milev et al 2017 with similar clinical phenotype: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings including pons hypoplasia, agenesis of the corpus callosum and brain atrophy. 2 of the 3 individuals had epilepsy with the third having a history of myoclonic jerks and significant MRI-B anomalies including agenesis of the corpus callosum. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12
Aslanger et al 2020 reports a 3rd case from an unrelated family with homozygous TRAPPC12 missense variants (reported previously by Milev et al in a patient with compound het variants) in a 2 year old M with axial hypotonia, appendicular hypertonia, severe dev delay, generalized tonic-clonic seizues and microcephaly. MRI-B showed ventriculomegaly, progressive severe cerebral atrophy, and moderate cerebellar atrophy.
Aslanger et al also report a 4th case from an unrelated family with a novel homozygous TRAPPC12 variant in a 9 year old M with severe truncal hypotonia, extreme hypertonicity, severe dev delay prominent cerebellar atrophy but no microcephaly or clinically apparent epilepsy. Paroxysmal discharges were noted on EEG. This case may reflect that the phenotype is more variable than previously anticipated particularly with biallelic missense variants however we would benefit from having more reported cases to expand the phenotype.Created: 11 Oct 2021, 12:02 a.m. | Last Modified: 11 Oct 2021, 12:02 a.m.
Panel Version: 0.1276
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Encephalopathy, progressive, early-onset, with brain atrophy and spasticity - 617669
Publications
I don't know
Comment when marking as ready: Three unrelated families with consistent phenotype including microcephaly and seizures.Created: 11 Oct 2021, 5:39 a.m. | Last Modified: 11 Oct 2021, 5:39 a.m.
Panel Version: 0.1286
Two unrelated families reported.Created: 25 Jan 2020, 9:31 a.m. | Last Modified: 25 Jan 2020, 9:31 a.m.
Panel Version: 0.498
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM#617669
Publications
Gene: trappc12 has been classified as Green List (High Evidence).
Gene: trappc12 has been classified as Green List (High Evidence).
Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM#617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM#617669
Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM#617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM#617669
Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM#617669
Publications for gene: TRAPPC12 were set to
Mode of inheritance for gene: TRAPPC12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Gene: trappc12 has been classified as Amber List (Moderate Evidence).
gene: TRAPPC12 was added gene: TRAPPC12 was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Australian Genomics Health Alliance Epilepsy Flagship,Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: TRAPPC12 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.