ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
29090079 Siper et al., 2017 - Authors describe 9 children and adolescents with variants in FOXP1, including 3 frameshift, one nonsense, and one splice variant demonstrated to result in skipping of the 8th coding exon, causing a frameshift. Additional variants were missense or in-frame deletion. Among the five reported LOF variants, four occurred de novo (c.1267_1268delGT, c.1333_1335delinsAA, c.1014dupA, c.975-2A>C) while the inheritance of the nonsense variant was unknown. Variants were identified by clinical exome sequencing (WES trios specified for two of the patients). Patients all presented with language and motor delays, ASD symptoms, hypotonia, mild gait abnormality, and variable dysmorphic facial features, among other characteristics. Psychiatric features included hyperactivity, impulsivity, aggression, irritability, and mood lability. Two of the patients with de novo LOF variants were previously reported (Lozano et al., 2015, and O?Roak et al., 2011).
20848658 Horn et al., 2010 - Report of 3 unrelated patients with heterozygous deletions involving only the FOXP1 gene, detected by microarray. Deletions were 498 kb, 659 kb and 1047 kb and included all but the first coding exon in Patient 1, and the entire coding region in Patients 2 and 3. Deletions occurred de novo in Patients 2 and 3; the deletion in patient 1 was absent in the mother, but father was unavailable for testing. Patients had ID and significant speech and language disorder. The group did also detect a single large deletion including FOXP1 and additional genes amongst 4104 ancestrally matched controls.
20950788 Hamdan et al. (2010) describe a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with non-syndromic intellectual disability (NSID) and autistic features. In addition, authors identified a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions.

Haploinsufficiency phenotype comments:

Palumbo et al. 2013 (PMID: 23287644) report another case of a deletion encompassing only FOXP1 in an adult individual with autism, severe speech delay, deficit of motor coordination and typical dysmorphic features. Carr et al., 2010 (PMID 20571508) report a 1.0Mb interstitial deletion of 3p14.1 that only involved the FOXP1 gene in a patient with speech and motor developmental delays, a Chiari I malformation, and epileptiform discharges. The deletion was identified by aCGH, and FISH testing of the parents showed it is de novo. Overall, these and other reports of de novo LOF variants in FOXP1 provide strong evidence of haploinsufficiency associated with ID, ASD, language impairment and other features. FOXP1 can also be included in larger interstitial deletions involving 3p14p12 resulting in a contiguous gene syndrome associated with short stature, failure to thrive, facial dysmorphism, congenital heart defects, urogenital abnormalities, neurological problems, hearing loss, and global developmental delay. See a detailed dissection of the critical regions for the various phenotypes in Dimitrov et al., 2014 (PMID 25908055).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No whole gene duplications involving the FOXP1 gene alone have been reported.