P2.82: Abnormal neuronal migration with ischemic brain injuries may cause cognitive dysfunction in extremely preterm infants

Heterozygous mutations in FOXG1 have been reported in patients with a congenital variant of Rett syndrome with varying brain malformations. FOXG1 encodes a winged helix transcriptional factor of the forkhead protein family which is mainly expressed in brain and regulates early steps in cortical development. The aim of this study was to search for mutations affecting the FOXG1 gene and to further delineate the clinical and brain imaging features of FOXG1-mutation positive patients. We report nine de novo mutations of FOXG1, including one previously described and eight novel alterations, consisting of two deletions, two chromosome rearrangements disrupting putative cis-regulatory elements, and five sequence changes among 189 patients tested. Adding these to prior reports, the mutational spectrum associated with FOXG1 mutations now includes six deletions and three other disruptions of chromosome 14q12, 12 null mutations (six nonsense, six frameshift), and only three missense mutations. Analysis of our nine patients and those in published reports demonstrates a complex constellation of clinical features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social interactions such as poor eye contact resembling autism, combined stereotypies and frank dyskinesias with mixed features of athetosis, chorea and dystonia, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastroesophageal reflux. Brain imaging studies reveal simplified gyral pattern over the frontal lobes, reduced white matter volume, corpus callosum hypogenesis, and variable mild frontal pachygyria. While this phenotype overlaps both classic and congenital Rett syndrome, extensive clinical data demonstrates a distinctive and clinically recognizable phenotype. We conclude that de novo mutations in FOXG1 are a rare cause of autosomal dominant mental retardation in patients with microcephaly and various brain malformations that can include frontal pachygyria and abnormal corpus callosum.