ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-29305
• Date last evaluated: 2021-03-09
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/2290
• OMIM: https://omim.org/entry/164874

Location Information

• 14q12
• GRCh37/hg19 chr14: 29,236,278-29,239,483

Evidence for Loss Phenotypes

• Loss of function score: 3
• Strength of Evidence: Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: FOXG1 Disorder

Evidence for loss of function phenotype

PubMed ID	Description
28661489	Mitter et al 2018 did a genotype-phenotype study of 83 patients with FOXG1 variants, including 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. In 65 patients from 63 families de novo occurrence was demonstrated by parental testing. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain and milder phenotypes with missense variants in the forkhead domain.
24836831	Seltzer et al 2014 report on the epilepsy features and developmental outcome of 23 new subjects with deletions (4 subjects, size 0.25?6.4 Mb including FOXG1) or intragenic variants of FOXG1 (19 subjects, with fifteen nonsense, frameshift, or intragenic insertions or deletions, and two missense mutations), and 7 subjects with duplications. Epilepsy was diagnosed in 87% of the subjects with FOXG1-related disorders. The mean age of epilepsy diagnosis in FOXG1 duplications was significantly younger than those with deletions/intragenic variants. Children with FOXG1 duplications and infantile spasms responded better to hormonal therapy than those with deletions or intragenic variants, who required anti-epileptic drugs on follow-up. All had neurodevelopmental disabilities after 3 years of age, regardless of the epilepsy type or intractability of seizures. Subjects with deletion/intragenic mutations had significantly worse ambulation and functional hand use.
29655203	Lindy et al 2018 studied the diagnostic outcomes in 8565 patients with epilepsy and NDD disorders by a 70-gene panel. Among them, 16 de novo sequencing variants in FOXG1 was identified, and 11 of these are truncating variants.
24139857	Kumakura et al. 2014 identified a de novo 540 kb deletion involving exon 1 of FOXG1 and C14orf23 (this gene is curated as a non-coding gene in the UCSC RefSeq curated subset) in a boy with FOXG1 disorder.
19578037	Mencarelli et al. (2010) identified 2 different de novo heterozygous truncating mutations in the FOXG1 gene in 2 unrelated girls with FOXG1 disorder. The first mutation is a 624C-G transversion, resulting in a tyr208-to-ter substitution. The second mutation is a 1 basepair insertion (552insC). Both girls had severe intellectual disability with lack of speech and motor development and stereotypic movements.
18571142

• Loss of function phenotype comments: From the ClinGen gene-disease validity evaluation: "Haploinsufficiency of the FOXG1 gene causes FOXG1 disorder, a condition sometimes referred to as the congenital variant of Rett syndrome. FOXG1 disorder, however, is a clinically distinct entity characterized by onset of neurodevelopmental impairment congenitally or during early infancy, in contrast to typical Rett syndrome in which symptoms appear after a period of normal development. Patients with FOXG1 disorder can also have epilepsy, motor dysfunction, stereotypic hand movements, abnormal breathing, lack of speech development, and corpus callosum hypoplasia on MRI." While large genomic deletions of FOXG1 have been demonstrated to cause FOXG1 disorder (Vineeth et al. 2018,PMID: 29920362; Cellini et al. 2016, PMID: 26344814; Bertossi et al. 2015, PMID: 25565401; Goubau et al. 2013 PMID: 23632790), accumulating evidence suggests that deletions involving FOXG1 downstream regulatory element region and the PRKD1 gene may also be associated with this phenotype (Caporali et al 2018, PMID: 29396177; Heide et al. 2017, PMID: 28284480; Alby et al. 2016, PMID: 26663670; Ellaway et al. 2013, PMID: 22968132).

Evidence for Triplosenstive Phenotype

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

• Triplosensitivity phenotype comment: There is not enough evidence of triplosensitivity of FOXG1 gene. The following are some literature of gains involving FOXG1 gene. PMID: 20736978. Brunetti-Pierri et al. 2010 identified 7 individuals with duplication (3.1 ~18 Mb) on chromosome 14q11.2q13.1, who exhibited idiopathic developmental delay and cognitive impairment, severe speech delay, and developmental epilepsy. Among these cases,. the ?3?Mb minimal duplicated region on chromosome 14q11.2q13.1 includes only three genes, FOXG1, C14orf23, and PRKD1. The author proposed that increased dosage of FOXG1 is the best candidate to explain the abnormal neurodevelopmental phenotypes observed in these patients. PMID: 24836831. Seltzer et al 2014 report on the epilepsy features and developmental outcome of 7 subjects with duplications and 23 new subjects with deletions (4 subjects, size 0.25?6.4 Mb including FOXG1) or intragenic variants of FOXG1 (19 subjects, with fifteen nonsense, frameshift, or intragenic insertions or deletions, and two missense mutations). The 7 subjects with duplications were most likely those reported in the Brunetti-Pierri et al. 2010 paper. The mean age of epilepsy diagnosis in FOXG1 duplications was significantly younger than those with deletions/intragenic variants. Children with FOXG1 duplications and infantile spasms responded better to hormonal therapy than those with deletions or intragenic variants, who required anti-epileptic drugs on follow-up. All had neurodevelopmental disabilities after 3 years of age, regardless of the epilepsy type or intractability of seizures. Subjects with deletion/intragenic mutations had significantly worse ambulation and functional hand use. PMID: 26542077. Kansal et al identified a 133 kb duplication involving the entire FOXG1 gene and compound heterozygous missense variants in MLH3 gene (a DNA mismatch repair gene) in a 4-month-old male infant presented with severe developmental delay, cerebellar, brainstem, and cutaneous hemangiomas, bilateral tumors (vestibular, hypoglossal, cervical, and lumbar spinal), and few caf?-au-lait macules. Author suspected that the FOXG 1 duplication might be a possible explanation for the developmental delay. Amor et al 2012 reported a small duplication involving only FOXG1 and C14orf23 (this gene is curated as a non-coding gene in the UCSC RefSeq curated subset) in a father-son pair who had only hemifacial microsomia. The father and son are phenotypically normal, have normal intellect, do not have epilepsy, and have no family history of epilepsy or cognitive impairment.

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.