Intellectual disability - microarray and sequencing
Gene: FOXP4 Amber List (moderate evidence)I don't know
Comment on gene rating: This gene should stay as AMBER as intellectual disability (ID) is not present in the majority of the affected cases displaying a variant in FOXP4 and the ID is mild in two of three cases reported with ID.
PMID:33110267 reported eight unrelated individuals with heterozygous variants in FOXP4. Detailed phenotypic information was only available for six of these cases. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Of these six individuals, two had mild ID, three had normal intellect and was unknown in the sixth case.
PMID:36301021 reported four individuals from two unrelated families (family 1: 2 years and 9 months old male child and his father; family 2: 12 years and 7 months old female child and her mother) with FOXP4 heterozygous variants. The phenotype of the affected children includes developmental delay, feeding difficulties in infancy, and similar facial features.The variant was inherited from a parent with mild or even subclinical features in both cases. Patient 1 presented with congenital diaphragmatic hernia, as reported in two other FOXP4 patients from PMID:33110267. Patient 1 is at risk of ID, while patient 2 has ID. However, father of patient 1 and mother of patient 2 (harbouring FOXP4 variant) did not have ID.
This gene has already been associated with phenotypes in Gene2Phenotype, but not in OMIM.Created: 27 Feb 2023, 2:55 p.m. | Last Modified: 27 Feb 2023, 2:55 p.m.
Panel Version: 4.79
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Green List (high evidence)
>=3 cases (there are 8 in the paper) and a convincing mechanism described (LOF shown by cellular reporter assays), the gene is a good ID candidate as a forkhead box TF (others involved in dominant ID/dysmo type conditions).
I also think the evidence for a LOF mechanism is pretty good, there is one termination variant in the paper, one more reported by James Lupski’s lab, it is highly constrained against LOF in gnomAD, and the functional evidence in the paper implicates a loss-of-protein function in the missenses.
+1 splicing variant identified in Peninsula GMC 100K case. De novo in compatible phenotype reported as diagnostic by SW GLH.Created: 8 Nov 2022, 2:21 p.m. | Last Modified: 8 Nov 2022, 2:21 p.m.
Panel Version: 3.1759
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.Created: 4 Dec 2020, 2:30 p.m. | Last Modified: 4 Dec 2020, 2:30 p.m.
Panel Version: 3.582
I don't know
This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel?
Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here.
Sources: LiteratureCreated: 4 Nov 2020, 3:27 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Neurodevelopmental disorder; multiple congenital abnormalities
Publications
Publications for gene: FOXP4 were set to 33110267; 36301021; 36646976
Publications for gene: FOXP4 were set to 33110267; 36301021; 36646976
Publications for gene: FOXP4 were set to 33110267; 36301021; 36646976
Publications for gene: FOXP4 were set to 33110267; 36301021; 36646976
Publications for gene: FOXP4 were set to 33110267; 36301021; 36646976
Publications for gene: FOXP4 were set to 33110267; 36301021; 36646976
Publications for gene: FOXP4 were set to 33110267; 36301021; 36646976
Publications for gene: FOXP4 were set to 33110267; 36301021; 36646976
Publications for gene: FOXP4 were set to 33110267
Tag gene-checked tag was added to gene: FOXP4.
Gene: foxp4 has been classified as Amber List (Moderate Evidence).
gene: FOXP4 was added gene: FOXP4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FOXP4 were set to 33110267 Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities Review for gene: FOXP4 was set to AMBER
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.