FOXG1 Syndrome: Genotype–Phenotype Association in 84 Patients with FOXG1 Variants

Background: The study aimed at widening the clinical and genetic spectrum and at assessing genotype–phenotype associations in FOXG1 syndrome due to FOXG1 variants.

Methods: We compiled a series of 31 new and 53 previously reported patients with a heterozygous variant in the FOXG1 gene. We grouped patients according to type and location of FOXG1 variants. Statistical analysis of molecular, clinical, and neuroimaging data was performed using Fisher´s exact test and a nonparametric multivariate test.

Results: Among the 31 new patients, we found 20 novel heterozygous FOXG1 variants. Taken all 84 patients together, there were 55 different variants including 20 frameshift (36%), 18 missense (33%), 15 nonsense (27%), and two in-frame variants (4%). Variants were distributed over all FOXG1 protein domains, with 19 variants in the N-terminal domain (35%), 11 variants in the forkhead conserved site 1 (20%), and 17 variants in the remaining forkhead domain (31%), and eight variants (15%) in the C-terminal domain. We found a higher phenotypic variability than expected from previous reports. Genotype–phenotype analysis revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the 5′ domain and the forkhead domain (except conserved site 1) and mildest phenotypes were found in patients with missense variants in the forkhead conserved site 1.

Conclusion: These data serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.