Intellectual disability
Gene: FOXP4

FOXP4 (forkhead box P4)
EnsemblGeneIds (GRCh38): ENSG00000137166
EnsemblGeneIds (GRCh37): ENSG00000137166
OMIM: 608924, Gene2Phenotype
FOXP4 is in 5 panels

4 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

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

Created: 27 Feb 2023, 2:55 p.m.
Last Modified: 27 Feb 2023, 2:55 p.m.
Panel version: 4.79

Ian Berry (Leeds Genetics Laboratory)

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

PMID: 33110267

Variants in this GENE are reported as part of current diagnostic practice

Created: 8 Nov 2022, 2:21 p.m.
Last Modified: 8 Nov 2022, 2:21 p.m.
Panel version: 3.1759

Ivone Leong (Genomics England Curator)

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

Created: 4 Dec 2020, 2:30 p.m.
Last Modified: 4 Dec 2020, 2:30 p.m.
Panel version: 3.582

Zornitza Stark (Australian Genomics)

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: Literature
Created: 4 Nov 2020, 3:27 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder; multiple congenital abnormalities

Publications

33110267

Created: 4 Nov 2020, 3:27 a.m.

Panel version: 3.510

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Amber

Phenotypes

Neurodevelopmental disorder
multiple congenital abnormalities

Tags

gene-checked

OMIM

608924

Clinvar variants

Variants in FOXP4

Penetrance

None

Publications

Panels with this gene