Intellectual disability - microarray and sequencing
Gene: ZBTB18 Green List (high evidence)Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.Created: 29 Sep 2018, 9:22 p.m.
Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.Created: 29 Sep 2018, 9:18 p.m.
Comment when marking as ready: Appropriate phenotype, sufficient cases with SNVs (de novo truncating and missense) in addition to the originally described chromosome deletion cases. Include.Created: 14 Nov 2017, 11:34 a.m.
Red List (low evidence)
Green List (high evidence)
>3 unrelated cases of ZBTB18 (also called ZNF238) supporting an ID phenotype (1st patient in PMID:23020937, 2nd patient in PMID:24193349, 3rd patient in PMID:26740508, 5 more patients in PMID:27598823).Created: 29 Nov 2017, 11:19 a.m.
PMID:27598823 (2017) report ZBTB18 as the likely cause of ID in 5 unrelated patients with variable syndromic features.Created: 16 Oct 2017, 10:10 a.m.
PMID:28345786 (2017) report a 6 year old girl with global developmental delay, ataxia and discrete facial dysmorphisms (amongst other symptoms). The patient had a de novo ZBTB18 nonsense mutation and a de novo 15q13.3 microdeletion (encompassing CHRNA7) both in a heterozygous state. The authors assume an additive effect of haploinsufficiency of ZBTB18 and CHRNA7 in the patient.Created: 16 Oct 2017, 10:09 a.m.
PMID:26740508 (2016) present a patient with severe ID, microcephaly, developmental regression, hand stereotypies, bruxism, screaming spells and abnormal breathing. She had a de novo truncating variant in ZBTB18 (c. 583C>T, p.R195*).Created: 16 Oct 2017, 10:09 a.m.
PMID:24193349 (2014) report a nonsensense variant (c.397 G>T, p.Glu133*) in ZBTB18 in a female patient with features overlapping including 1q43q44 microdeletion syndrome (except for a normal corpus callosum), including microcephaly (-2 SD), pronounced speech delay and global DD.Created: 16 Oct 2017, 10:08 a.m.
In PMID:23020937 (2012, an exome sequencing study of ID) a female patient with severe non-syndromic ID and normal neuroimaging was found to have a de novo missense alteration, c.1483C>G (p.R495G), in transcript NM_205768.2 [reported as c.1456C>G (p.R486G) based on the non-preferred transcript NM_006352.3]. The authors proposed ZNF238 (ZBTB18) as a candidate gene for ID.Created: 16 Oct 2017, 10:07 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
intellectual disability with variable features; global developmental delay; Mental retardation, autosomal dominant 22, 612337
Publications
Green List (high evidence)
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : NACreated: 27 Jul 2017, 8:57 p.m.
Mode of inheritance
Unknown
Publications
Red List (low evidence)
Gene: zbtb18 has been classified as Green List (High Evidence).
Gene: zbtb18 has been classified as Green List (High Evidence).
Source Victorian Clinical Genetics Services was added to ZBTB18.
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Publications for ZBTB18 were set to 28345786; 27598823; 24193349; 23020937; 26740508; 25529582
Expert Review Green was added to ZBTB18. Panel: Intellectual disability Model of inheritance for gene ZBTB18 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene ZBTB18 was set to ['28345786', ' 27598823', ' 24193349', ' 23020937', ' 26740508']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ZBTB18 was created by ellenmcdonagh
ZBTB18 was added to Intellectual disabilitypanel. Sources: Expert Review Red
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.