ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-21932
• Date last evaluated: 2020-07-29
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/2296
• OMIM: https://omim.org/entry/601090

Location Information

• 6p25.3
• GRCh37/hg19 chr6: 1,610,681-1,614,132

Evidence for Loss Phenotypes

• Loss of function score: 3
• Strength of Evidence: Sufficient evidence for dosage pathogenicity
• Haploinsufficiency phenotype: AXENFELD-RIEGER SYNDROME, TYPE 3; RIEG3

Evidence for loss of function phenotype

PubMed ID	Description
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.
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.
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.

• Loss of function phenotype 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.

Evidence for Triplosenstive Phenotype

• Triplosensitivity score: 0
• Strength of Evidence: No evidence for dosage pathogenicity
• Triplosensitivity phenotype: ANTERIOR SEGMENT DYSGENESIS 3; ASGD3

• Triplosensitivity phenotype comment: 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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.