Delineating FOXG1 syndrome: From congenital microcephaly to hyperkinetic encephalopathy

Abstract

Objective: To provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome.

Methods: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations.

Results: A total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.

Conclusions: These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

Figure 1. Schematic representation of FOXG1 gene, protein domain structure, and positions of FOXG1 mutations

(A) Schematic representation of FOXG1 gene and (B) FOXG1 protein domain structure and positions of the variations identified: N-terminal domain; FBD domain (forkhead DNA binding domain, amino acids 181–275), GBD domain (Groucho binding domain, amino acids 307–317), JBD domain (JARID1B binding domain, amino acids 383–406), and C-terminal domain are indicated. Mutations are located all along the FOXG1 gene, within different protein domains. Missense mutations are predominantly located in the FBD (91.7%), whereas frameshift mutations are more prominent in the N-terminal domain (57.1%). The novel variants described in this article are highlighted in bold and the recurrent variants are underlined with the corresponding number of recurrences indicated in brackets. FBD = forkhead binding domain; GBD = Groucho binding domain; JBD = JARID1B binding domain.

Figure 2. Representative MRI of pachygyric frontal cortex in FOXG1 patients

Representative images at the level of centrum semiovale in axial T1-weighted (A, E, I) and T2-weighted (B, F, J) MRI, at the level of lateral ventricles (third column) and midline sagittal (right column). Each row shows images from the same patient respectively: (A–D) Str02 aged 19 months; (E–H) Ang01 aged 23 months; (I–L) Rou01, aged 34 months. The cortex appears mildly thick with a clear predominance in the frontal lobes. The appearance of pachygyria is accentuated by the underdevelopment of frontal lobes. T2-weighted (C, G, K) MRI at the level of the internal capsule showing associated myelination delay, with mature myelin only visible in both internal capsules (G and K). T1-weighted midline sagittal sections showing the wide range of appearance of the corpus callosum, from hypoplastic and thin (D, L) to thick with underdevelopment of the genu (H).

Figure 3. Changing appearance of the frontal cortex with age associated with increasing myelination

Representative images from 2 patients: Im11 p.Gln86Profs*35 (A–D) and Im09 p.Glu154Glyfs*301 (E–H). (A and B) Images obtained when the patient was 6 months old. T2-weighted image (A) shows normal thickness of both frontal lobes but delayed myelination. T1-weighted image (B) shows a pachygyric cortex in the same region. (C and D) Images obtained when the patient was 2 years 6 months. T2-weighted image (C) of the frontal lobe shows mildly thickened cortex, probably because of the poor myelination of the subcortical white matter. (E and F) Images obtained when the patient was 1 year 8 months. In the frontal lobe, T2-weighted (E) and T1-weighted (F) images show the same pattern of pachygyric cortex and severely delayed myelination (E). (G and H) At 3 years, the T2-weighted image (G) shows significant improvement of myelination, although still delayed in the frontal subcortical region: the T1-weighted image (H) shows mildly simplified gyral pattern, with no pachygyria.