Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment

Abstract

Genome-wide high-resolution array analysis is rapidly becoming a reliable method of diagnostic investigation in individuals with mental retardation and congenital anomalies, leading to the identification of several novel microdeletion and microduplication syndromes. We have identified seven individuals with duplication on chromosome 14q11.2q13.1, who exhibited idiopathic developmental delay and cognitive impairment, severe speech delay, and developmental epilepsy. Among these cases, the minimal common duplicated region on chromosome 14q11.2q13.1 includes only three genes, FOXG1, C14orf23, and PRKD1. We propose that increased dosage of Forkhead Box G1 (FOXG1) is the best candidate to explain the abnormal neurodevelopmental phenotypes observed in our patients. Deletions and inactivating mutations of FOXG1 have been associated with a Rett-like syndrome characterized by hypotonia, irritability, developmental delay, hand stereotypies, and deceleration of head growth. FOXG1, encoding a brain-specific transcription factor, has an important role in the developing brain. In fact, in vivo studies in chicken brain demonstrated that overexpression of FOXG1 results in thickening of the neuroepithelium and outgrowth of the telencephalon and mesencephalum, secondary to a reduction in neuroepithelial cell apoptosis.

Figure 1

Facial appearance of individuals with the duplication involving 14q11.2q13.1 (a: patient 1; b: patient 2; c: patient 3; d: patient 4; e: patient 5; f: patient 6; g: DECIPHER case 248559). Patients 2, 6, and DECIPHER 248559 have facial dysmorphisms. Patient 1, 4, and 5 are non-dysmorphic. Only mild dysmorphisms are seen in patient 3.

Figure 2

Brain MRI of patient 1 showed an intact anterior corpus callosum (arrow) (a) and mildly foreshortened frontal lobes (b). Brain MRI of patient 3 showed thin corpus callosum (arrow) (c), reduction in white matter volume, large lateral ventricles, and increased periventricular white matter signal (d).

Figure 3

Schematic representation of chromosome 14q11.2q13 duplications and the minimally duplicated region (gray shadow) in the seven presented cases (not drawn to scale). Each duplication is shown as a green bar. Benign CNV found in DECIPHER case 1366 is shown as a light blue bar. Triplication (from nucleotide 30 780–31 138 kb) found in patient 4 is shown as a pink bar and overlaps to a known benign copy number polymorphism (database of genomic variants: http://projects.tcag.ca/variation).