Intellectual disability - microarray and sequencing
Gene: EPB41L1 Amber List (moderate evidence)I don't know
Hamdan et al. (PMID: 21376300) reported on a boy with ID and a de novo EPB41L1 variant. The authors performed functional studies to show that the protein encoded by this gene (4.1N), when mutated, presents reduced binding (by 50%) to the AMPA Receptor subunit GluR1 in transfected HEK293 cells. Insertion of the GluR1 at the synaptic membrane was significantly decreased in transfected hippocampal neurons producing the mutant protein, compared to wild-type. The proband had the Pro854Ser (NM_012156.2:c.2560C>T) variant. Concerning the specific variant ClinVar cites 2 further articles on the role of 4.1N on AMPARs (PMIDs : 19503082, 11050113).
ClinVar has a single further submission of a likely pathogenic variant p.Arg638Cys (NM_001258329.1:c.1912C>T) associated with abnormality of brain morphology. This entry cites a publication from the submitter (Karaca et al. - PMID: 26539891). In the supplement of this article the variant appears to be associated with frontotemporal dementia (considered as expansion of the phenotype).
In denovo-db there appear to be 2 patients with de novo variants, with the phenotype of ASD and SCZ respectively. The patient with ASD was published in the context of a larger ASD cohort by Krumm et al. (PMID: 25961944). This individual (13771.p1) had a further de novo SNV in KIAA1009 and was reported to have a full-scale IQ of 83 (supplement).
There appears to be no other relevant patient reported in the literature.
There are no relevant patients in Decipher (SNVs or small CNVs).
In OMIM this gene is associated with ?Mental retardation, autosomal dominant 11 (MIM 614257) based on the article by Hamdan et al.
EPB41L1 is still a possible DD gene in G2P associated with intellectual disability.
The gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
As a result this gene should probably remain amber.Created: 20 Dec 2018, 8:39 a.m.
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
I don't know
A heterozygous missense variant was reported in PMID 21376300. This is a possible DD gene for ID in Gene2Phenotype. This gene is included in the 20q11.2 microdeletion reported in PMID: 25572454, along with other genes, and disruption of this gene was suggsted to underly the ID in these patients.Created: 27 Oct 2017, 2:46 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
?Mental retardation, autosomal dominant 11 614257
Publications
Red List (low evidence)
Source: Expert Review Red was removed from gene: EPB41L1
Source Victorian Clinical Genetics Services was added to EPB41L1.
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.
Expert Review Amber was added to EPB41L1. Panel: Intellectual disability Model of inheritance for gene EPB41L1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene EPB41L1 was set to ['21376300', '25572454']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
EPB41L1 was added to Intellectual disabilitypanel. Source: Expert Review Red
EPB41L1 was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen
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.