• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
FOXC1 (HGNC:3800) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
forkhead box C1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
FKHL7, IRID1
Alias symbols
FREAC3, ARA, IGDA, IHG1
%HI
9.01(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.95(Read more about gnomAD pLI score)
LOEUF
0.31(Read more about gnomAD LOEUF score)
Cytoband
6p25.3
Genomic Coordinates
GRCh37/hg19: chr6:1610150-1614132 NCBI Ensembl UCSC
GRCh38/hg38: chr6:1609915-1613897 NCBI Ensembl UCSC
MANE Select Transcript
NM_001453.3 ENST00000645831.2 (Read more about MANE Select)
Function
DNA-binding transcriptional factor that plays a role in a broad range of cellular and developmental processes such as eye, bones, cardiovascular, kidney and skin development (PubMed:11782474, PubMed:15299087, PubMed:15684392, PubMed:16492674, PubMed:27907090, PubMed:14506133, PubMed:14578375, PubMed:15277473, PubMed:16449236, PubMed:17210863, PubMed:19793056, PubMed:19279310, PubMed:25786029, PubMed:27804176). Acts either as a transcriptional activator or repressor (PubMed:11782474). Binds to th... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-21932
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
07/29/2020

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Axenfeld-Rieger syndrome type 3 Monarch
HI Evidence:
  • PUBMED: 11170889
    In 2001, Nishimura et al. used sequencing and SSCP analysis on 70 individuals with congenital anterior-chamber defects of the eye for potential FOXC1 variants. These patients had already been screened for causative PITX2 variants and had received negative results. Analysis of FOXC1 identified 9 variants. Per the authors, “Five of these mutations cause a translational-reading-frame alteration that results in premature termination of the FOXC1 transcript.” For 2 of these variants, segregation was documented to 1 other affected family member. For the other 3 variants, inheritance information was not reported.
  • PUBMED: 17653043
    In 2007, Fuse et al. used PCR on a family with Axenfeld-Rieger syndrome to identify potential variants in FOXC1. Analysis discovered a frameshift variant in the proband and her father. This variant is predicted to result in protein truncation, with the protein consisting of 298 amino acids instead of 553 amino acids.
  • PUBMED: 16936096
    In 2006, Weisschuh et al. used PCR on 19 patients in 13 families with anterior segment dysgenesis to identify potential variants in PITX2 and FOXC1. Analysis identified 2 frameshift variants leading to premature termination of translation. The authors also identified a nonsense variant leading to protein truncation in another patient.
HI Evidence Comments:
Axenfeld-Rieger syndrome, type 3 Additional articles: PMID: 31410177 In 2019, Wu et al. used next generation sequencing (NGS) on a family with Axenfeld-Rieger syndrome (ARS). Analysis identified a frameshift variant (p.G499Afs*20) resulting in protein truncation in FOXC1 in the proband and her affected father. PMID: 32499604 Published in 2020, Ma et al. used next generation sequencing (NGS) on 41 individuals with ocular anterior segment disorders (ASDs). Analysis identified a nonsense variant (p.Gln467*) in FOXC1 in an individual who also had intellectual disability (ID) and a confirmed de novo frameshift variant (p.Met161Ilefs*22) in another individual who also had developmental delay as part of his phenotype. Per the authors, “For both patients, other causes of intellectual delay were not found following baseline testing with chromosome microarray, urine metabolic screen, and fragile X testing, or ES reanalysis for causative variants in known ID genes (Genomics England PanelApp, https://panelapp.genomicsengland.co.uk, Intellectual disability [Version 2.1046]).” The patient with the nonsense variant was a sporadic case of ASD but whether the variant was de novo was not confirmed. PMID: 12592227 In 2003, Komatireddy et al. used PCR and direct sequencing on 10 unrelated families with Axenfeld-Rieger anomaly (ARA) to search for causative FOXC1 variants. Analysis identified FOXC1 variants in 3 cases, 1 case involving a missense variant and 2 cases involving nonsense variants. In 1 family, the nonsense variant p.Q123X was identified in the proband and 2 affected family members. Per the authors, “The unaffected grandmother (ARA7G) of the proband in this family was also found to harbor the same mutation and had the 1-1-1 affected haplotype (Figure 2A).” The other nonsense variant identified in this study (p.Q2X) was a sporadic case, but inheritance does not appear to be confirmed. Of note, an individual with a variant in OXT2 was described to have a complex phenotype by Avasarala et al. (PMID: 29751260). In 2018, Avasarala et al. described an individual with a complex phenotype including Meniere’s disease, glaucoma, and cerebral small-vessel disease (CSVD) and who was suspected at one point of having multiple sclerosis. The son was also described who, per the authors, “had dysmorphic facies and was small for age. He had a bifid uvula, bilaterally duplicated thumbs and scoliosis. Additionally, he had hypertelorism, a wide forehead and flattening of mid-face.” Whole exome sequencing on the son revealed a likely pathogenic frameshift variant (p.Asp117Thrfs*64) resulting in a premature stop codon in FOXC1. This same variant was also identified in the mother.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
While single-gene duplications have not been reported, included here are cases of duplications involving multiple genes including FOXC1. PMID: 11007653 Lehmann (2000) identified a chromosomal duplication that involves FOXC1 and segregates with the phenotype in a multi-generation family with an AD form of iris hypoplasia and glaucoma. PMID: 18694899 Chanda (2008) fine-mapped a series of duplications by microarray, including the duplication from the Lehmann 2000 report. The duplications included 3-4 genes. PMID: 11170889 Nishimura (2001) identified a duplication including FOXC1 in a family with 4 individuals affected with iris hypoplasia. The duplication segregated with disease. A second duplication including FOXC1 was identified in a second family with a proband with Peters anomaly. Since the duplication was not fine-mapped (this reference was not listed in the pedigree table in Chanda et al. 2008), it is unclear as to whether additional genes are involved in the duplication and are responsible for the phenotype. PMID: 12036988 Lehmann (2002) identified a duplication including FOXC1 in a family with iris hypoplasia. Since the duplication was not fine-mapped (this reference was not listed in the pedigree table in Chanda et al. 2008), it is unclear as to whether additional genes are involved in the duplication and are responsible for the phenotype.

Genomic View

Select assembly: (NC_000006.11) (NC_000006.12)