Intellectual disability - microarray and sequencing
Gene: TBC1D20 Green List (high evidence)Comment on list classification: Updated rating from Grey to Green. Gene added to panel and reviewed Green by Konstantinos Varvagiannis. 5 unrelated families (7 individuals) reported in PMID:24239381 (Liegel et al, 2013) with 5 different homozygous TBC1D20 loss of function variants, and all with profound or severe mental retardation and developmental delay (Supplementary table S4).Created: 26 Feb 2019, 12:15 p.m.
Comment on mode of inheritance: Biallelic MOI supported by OMIM and PMID:24239381.Created: 26 Feb 2019, 12:13 p.m.
Comment on publications: PMID:26063829 demonstrates biochemically that TBC1D20 is a regulator of RAB18 (associated with Warburg micro syndrome 3, 614222).Created: 26 Feb 2019, 12:11 p.m.
Green List (high evidence)
Biallelic pathogenic variants in TBC1D20 cause Warburg Micro syndrome 4 (MIM 615663).
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Liegel et al. (PMID: 24239381) report on 7 individuals from 5 unrelated families. ID was a universal feature along with opthalmological, endocrine and other neurological features of the disorder. Seizures were noted in 4 individuals from 2 families. Table S4 of this article provides clinical details on each subject.
All affected individuals were homozygous for LoF variants, private to each family. 3 nonsense variants, 1 frameshift one as well as an intragenic deletion (exons 2-8) were identified.
These subjects belonged to a cohort of 77 individuals with suspected Warburg Micro syndrome (WMS) or disorders of the same spectrum (eg. Martsolf syndrome).
Screening for TBC1D20 mutations in these individuals was performed after identification of a homozygous LoF Tbc1d20 mutation in blind sterile mice, presenting a phenotype somewhat similar to WMS (congenital cataracts and testicular anomalies).
Alternative causes of WMS (eg. pathogenic variants in RAB3GAP1, RAB3GAP2 and RAB18) had previously been excluded in this cohort.
The authors demonstrated aberrant lipid droplet formation in embryonic fibroblasts from blind sterile mice as well as in fibroblasts from individuals with a diagnosis of WMS due to mutations in either of TBC1D20, RAB18 and RAB3GAP1.
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TBC1D20 is included in the DD panel of G2P, associated with Warburg micro syndrome 4 (Disease confidence: probable / ID among the phenotypes assigned to this entry).
This gene is included in gene panels for ID offered by different diagnostic laboratories (incl. Radboudumc).
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As a result, TBC1D20 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature, Radboud University Medical Center, NijmegenCreated: 1 Jan 2019, 11:51 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Warburg Micro syndrome 4 (MIM 615663)
Publications
Variants in this GENE are reported as part of current diagnostic practice
Gene: tbc1d20 has been classified as Green List (High Evidence).
Mode of inheritance for gene: TBC1D20 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D20 were set to 24239381; 26063829
Phenotypes for gene: TBC1D20 were changed from Warburg Micro syndrome 4 (MIM 615663) to Warburg micro syndrome 4, 615663; mental retardation; developmental delay
gene: TBC1D20 was added gene: TBC1D20 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: TBC1D20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBC1D20 were set to 24239381; 26063829 Phenotypes for gene: TBC1D20 were set to Warburg Micro syndrome 4 (MIM 615663) Penetrance for gene: TBC1D20 were set to Complete Review for gene: TBC1D20 was set to GREEN gene: TBC1D20 was marked as current diagnostic
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 [email protected]
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.