ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

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Evidence for Loss Phenotypes

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.

Evidence for Triplosenstive 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.