Delineating FOXG1 syndrome

Abstract

ObjectiveTo provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome.MethodsWe 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.ResultsA 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.ConclusionsThese 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.

Transcription and Beyond: Delineating FOXG1 Function in Cortical Development and Disorders

“…At the genomic level, patients presenting with FOXG1 syndrome display heterozygous variants that harbor de novo mutations ranging from truncating, frameshift, nonsense, missense mutations, to duplications in the 14q12 FOXG1 gene locus (Yeung et al, 2009;Brunetti-Pierri et al, 2011;Seltzer et al, 2014). Such a genetic spectrum of FOXG1 mutations was broadened by two parallel analyses that employed sequencing of a large cohort of patients with FOXG1 variants (Mitter et al, 2018;Vegas et al, 2018). Mitter et al (2018) studied 83 patients that included 54 variants and identified 20 frameshift mutations (37%), 17 missense mutations (31%), 15 nonsense mutations (28%), and 2 in-frame mutations (4%).…”

“…Mitter et al (2018) studied 83 patients that included 54 variants and identified 20 frameshift mutations (37%), 17 missense mutations (31%), 15 nonsense mutations (28%), and 2 in-frame mutations (4%). Vegas et al (2018) reported 37 FOXG1 heterozygous mutations including 18 novel mutations with 32 small intragenic mutations and five large deletions in the FOXG1 gene locus. In this study, a similar frequency of respective mutations was observed: four frameshift (44%), 12 missense (38%), and a minor population of nonsense (4; 13%), and in-frame mutations (2; 6%), indicating the overall contribution of FOXG1 coding region mutations to neurological symptoms.…”

Diagnosis of FOXG1 syndrome caused by recurrent balanced chromosomal rearrangements: case study and literature review

“…FOXG1 syndrome results from intragenic or intergenic mutations resulting in haploinsufficiency of FOXG1. FOXG1 syndrome has a well-defined clinical phenotype characterized in numerous case reports and cohort studies as postnatal growth restriction, post-natal microcephaly, global developmental delay with absence of language, movement disorder characterized by chorea and dystonia, deficient social reciprocity, variable forms of epilepsy, poor sleep patterns, paroxysmal laughter/crying, recurrent aspiration, with common neuroimaging findings of simplified gyral patterning reduced white matter frontal lobe volume, hypogenesis of the corpus callosum, and delayed myelination [8,[16][17][18].…”

FOXG1-Related Syndrome: From Clinical to Molecular Genetics and Pathogenic Mechanisms

“…This allows further expansion and delineation of the clinical phenotypes of FOXG1 mutations, thus progressing parting from RTT. Compared to RTT, individuals with FOXG1 mutations generally lack ‘eye gazing/pointing’, are more severe in language, ambulation, social interaction, and sleeping disturbance, and most importantly, lack of the regression as observed in RTT [6,9,10,11,12,13].…”

“…To date, there are more than 120 different mutations, including deletions, intragenic mutations, and duplications, of FOXG1 have been reported worldwide [4,6,10,11,12,16,17,18,19,20,21,22,23,24,25,26,27]. In addition to clinical studies, both in vivo and in vitro studies have been performed to delineate the function of FOXG1 and pathogenic mechanisms underlying this syndrome.…”