FOXP1

Inheritance Pattern: AD

Disease ID:MONDO:0013352

Submitter: Illumina

The FOXP1 gene is located on chromosome 3 at 3p13 and encodes the forkhead box P1 protein, which is a transcriptional repressor that promotes columnar organization of spinal motor neurons and plays a role in specification and differentiation of lung epithelium, regulation of B-cell development and cardiac muscle cell proliferation. The FOXP1 gene was first reported in relation to autosomal dominant FOXP1-related intellectual disability syndrome in 2010 (20950788: Hamdan et al. 2010). At least six unique variants have been reported in humans, including missense and predicted null variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands in three publications (20950788: Hamdan et al. 2010; 26647308: Sollis et al. 2016; 28735298: Meerschaut et al. 2017). All variants occurred de novo. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease involves haploinsufficiency. This gene-disease relationship is also supported by expression data, in vitro functional assays, and data from a knockout mouse model (12687690: Ferland et al. 2013; 26647308: Sollis et al. 2016). In summary, FOXP1 is definitively associated with autosomal dominant FOXP1-related intellectual disability syndrome.

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*FOXP1* was first reported in relation to autosomal dominant congenital heart disease in 2013 (Chang et al., 23766104). For this curation, variants in FOXP1 have been reported in individuals with the following phenotypes: atrioventricular septal defect and hypoplastic left heart syndrome. Of note, this gene has also been implicated in intellectual developmental disorder with language impairment with or without autistic features (OMIM:613670) and congenital anomalies of the kidney and urinary tract (CAKUT). These will be assessed separately. At least 3 variants (missense, deep intronic deletion, and a large deletion) have been reported in humans (23766104, 33084842). Evidence disputing this gene-disease relationship includes case-level data. Of the three variants reported, one is too frequent to cause disease, another is a deep intronic deletion with unknown functional consequence, and the third is a large deletion that encompasses microRNA hsa-miR-1284 and was inherited from an unaffected parent; therefore, none of the published genetic evidence was scorable. This gene-disease relationship is supported by animal models and expression studies (15342473). In summary, due to the lack of convincing genetic evidence, the evidence supporting the relationship between *FOXP1* and autosomal dominant congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *FOXP1* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date December 11, 2023 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0013352

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0013352

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013352

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0013352

Submitter: ClinGen

*FOXP1* was first reported in relation to autosomal dominant intellectual disability-severe speech delay-mild dysmorphism syndrome in 2010 (Carr et al., 20571508; Hamdan et al., 20950788; Horn et al., 20848658). Fourteen variants (missense, nonsense, frameshift, splice, and large intragenic deletions) that have been reported in 16 probands in 11 publications (PMIDs: 20950788, 24083349, 24214399, 25767709, 25853299, 26647308, 27657687, 28884888, 29330474, 30385778, 30631761) are included in this curation. Most variants occurred *de novo*. Missense variants that were common in gnomAD were not scored. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is aso supported by animal models and *in vitro* functional assays. In summary, there is definitive evidence supporting the relationship between *FOXP1* and autosomal dominant intellectual disability-severe speech delay-mild dysmorphism syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 9, 2019 (SOP Version 6).

Inheritance Pattern: AD

Disease ID:MONDO:0013352

Submitter: Ambry Genetics