The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis

Abstract

Background: Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients.

Method: The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals.

Results: One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria.

Conclusions: These findings have significantly expanded the number of FOXG1 mutations and identified two affecting possible cis-regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.

Figure 1

Brain imaging in a normal 3-year-old girl (A–D) and four patients with FOXG1 mutations (E–T). Here and in figure 2, each row shows four images from the same patient. The columns contain midline sagittal (left column) and parasagittal (2nd column) images, and axial images through the lateral ventricles (3rd column) and high convexity (right column). All four patients have a low forehead that reflects underlying microcephaly, foreshortened frontal lobes and reduced white matter volume that appears severe in the frontal lobes (asterisks in 12/16 images) and subtle in posterior regions. All four have hypogenesis of the anterior corpus callosum with a “pointed hook” appearance in three of them (arrows in E, M, Q) that consists of striking narrowing of the anterior body, genu and rostrum with the tiny rostrum forming a pointed tip, and relatively normal posterior callosum. In the remaining patient (arrow in I), the entire body of the corpus callosum is narrow and the genu small but less so than the others, leaving it dysmorphic but different from the “pointed hook” appearance. Three patients have subtle pachygyria over the frontal lobes only that consists of mildly short and wide gyri and mildly thick cortex (arrowheads in F–H, J–L, N–P), a subtle abnormality that may be accentuated by the reduced volume of the white matter. The increased cortical thickness was not seen in the remaining patients (R–T and Figure 2). Also, three patients had mildly enlarged lateral ventricles, with one having abnormally narrow anterior body and frontal horns (S). These images come from patients 1 (E–H), 5 (I–L), 7 (M–P) and 9 (Q–T), and a normal control (A–D).

Figure 2

Brain imaging in another six patients with FOXG1 mutations. Five have mildly enlarged lateral ventricles. The patients in the top four rows have changes similar to those seen in Figure 1, including microcephaly (E, I, M; not obvious in A, Q), short frontal lobes and reduced volume of frontal white matter (asterisks in 8/16 images). Hypogenesis of the corpus callosum was seen in 4/5, but with different patterns. The first patient (A) has a thin and dysmorphic corpus callosum similar to Figure 1I, the next total agenesis of the corpus callosum (E), and the third and fourth partial agenesis with a short and thin corpus callosum (I, M). No patients in this group have pachygyria. The last two patients have normal brain imaging except for subtle reduced volume of the frontal white matter and mildly simplified gyral pattern. These images come from patients 6 (A–D), 3 (E–H), 2 (I–L), 10 (M–P), 4 (Q–T), and 11 (U–X).

Figure 3

Deletions including FOXG1 and regulatory mutations. (A) Physical map of the 14q12-q13.1 region. Genes in this region are represented by arrows indicating the 5’ 3’ orientation. Fosmid clones (F- [G248P8]; WIBR-2 Human Fosmid Library) used for mapping the 14q12 breakpoint of the 2;14 translocation in patient 1 (1) are indicated by colored bars and names are given. Color code of fosmids; black: mapped distal to the translocation breakpoint; blue: spanned the breakpoint; green: mapped proximal to breakpoint. The breakpoint region is indicated by a wavy vertical arrow in red. (B) Deletions in 14q12. Horizontal black lines depict the deletions identified in patients 2 – 4 (2, 3, 4). Arrowheads at the left and right side of the deletion in patient 2 show that this deletion extends to either side. Dotted lines indicate that the respective deletion breakpoints have not been fine-mapped. BAC clones (RP11 Human BAC Library) used for FISH analysis to confirm the presence of the deletions in the patients are indicated by red bars and names are given. (C) A detailed view of the region containing putative long-range cis-regulatory elements of FOXG1. In the upper part, the two black vertical bars represent potential regulatory elements (genomic positions chr14:28,754,647-28,756,495 bp and 28,930,280-28,932,099 bp) that have been identified with the ESPERR (evolutionary and sequence pattern extraction through reduced representations) computational method. In the lower part, a more detailed view of the region of high Regulatory Potential (RP) values, with the UCSC genome browser map of seven-way (human, chimpanzee, macaque, mouse, rat, dog, and cow; March 2006 assembly) RP analysis of the candidate cis-regulatory elements distal to FOXG1.

Figure 4

Patients with FOXG1 mutations. Two patients with 14q12 deletions (top row, A–B) demonstrate mild facial dysmorphism consisting of round face with flat midface, low nasal bridge, bulbous nasal tip, thin upper lip and prominent ears (A–B). Four children with regulatory (top row, C and bottom row, D) or intragenic mutations (bottom row, E–F) have normal facial appearance except for mildly prominent ears. One photo shows hand stereotypy (D), and another shows striking esotropia (F). These patient numbers and mutations are shown at the bottom of each photo.