Intellectual disability - microarray and sequencing
Gene: NEDD4L Green List (high evidence)The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Green List (high evidence)
Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases with a severe developmental delay phenotype for it to be rated green. It should therefore be reviewed at the next GMS update.Created: 8 Oct 2020, 8:58 p.m. | Last Modified: 8 Oct 2020, 8:58 p.m.
Panel Version: 3.409
Associated with Periventricular nodular heterotopia 7 #617201 (AD) in OMIM.
PMID: 27694961 - Broix et al 2016 - report 4 different de novo missense changes in NEDD4L in a total of five unrelated patients with periventricular nodular heterotopia and neurodevelopmental delay, and in a additional familial case with a similar phenotype and a previously found missense variant. In the familial case, two affected siblings were found to be heterozygous for the variant, the father and an unaffected sibling did not carry the variant, and the mother was found to show somatic mosaicism of NEDD4L variant. Functional studies showed a sensitivity of PNH-associated mutants to proteasome degradation. Seizures were reported in some but not all affected individuals.Created: 8 Oct 2020, 8:51 p.m. | Last Modified: 8 Oct 2020, 9:01 p.m.
Panel Version: 3.410
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Periventricular nodular heterotopia 7, 617201
Publications
Green List (high evidence)
Developmental delay reported in all individuals in this series, and described as severe in several.Created: 5 Mar 2020, 7:36 a.m. | Last Modified: 5 Mar 2020, 7:36 a.m.
Panel Version: 3.3
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Periventricular nodular heterotopia 7, MIM#617201
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
Variants in this gene have been linked to Epileptic Encephalopathy, with a denovo mutation in one female out of 264 patients with infantile spasms or Lennox-Gastaut syndrome. Patient did display some mental regression, however unsure if this was due to the seizures or direct genetic impact. Evidence for variants in different genes noted in the study stronger than this link.Created: 7 Mar 2018, 2:55 p.m.
Publications
Red List (low evidence)
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
EPILEPTIC ENCEPHALOPATHY
Publications
Red List (low evidence)
Tag for-review was removed from gene: NEDD4L.
Source Expert Review Green was added to NEDD4L. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag for-review tag was added to gene: NEDD4L.
Gene: nedd4l has been classified as Amber List (Moderate Evidence).
Gene: nedd4l has been classified as Red List (Low Evidence).
Phenotypes for gene: NEDD4L were changed from EPILEPTIC ENCEPHALOPATHY to Periventricular nodular heterotopia 7, 617201
Publications for gene: NEDD4L were set to 23934111
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.
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
NEDD4L was created by ellenmcdonagh
NEDD4L 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.