ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-29305
• Date last evaluated: 2012-03-08
• 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: RETT SYNDROME, CONGENITAL VARIANT

Evidence for loss of function phenotype

PubMed ID	Description
18571142	Ariani et al. (2008) identified 2 different de novo heterozygous truncating mutations in FOXG1 in 2 unrelated girls: the first mutation is a 765G-A transition resulting in a trp255-to-ter substitution, and the second mutation is a 1 basepair deletion (969delC). Both girls had the congenital variant of Rett syndrome (infantile onset on microcephaly, intellectual disabilities, and stereotypic movements similar to that observed in classic Rett syndrome).
19578037	Mencarelli et al. (2010) identified 2 different de novo heterozygous truncating mutations in the FOXG1 gene in 2 unrelated girls with the congenital variant of Rett syndrome. 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.

• Loss of function phenotype comments: Heterozygous loss of FOXG1 results in the congenital variant of Rett syndrome (see OMIM).

Evidence for Triplosenstive Phenotype

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

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.