Epilepsy phenotype in individuals with chromosomal duplication encompassing FGF12

Abstract

Intragenic mutations in FGF12 are associated with intractable seizures, developmental regression, intellectual disability, ataxia, hypotonia, and feeding difficulties. FGF12 duplications are rarely reported, but it was suggested that those might have a similar gain-of-function effect and lead to a more or less comparable phenotype. A favorable response to the sodium blocker phenytoin was reported in several cases, both in patients with an intragenic mutation and in patients with a duplication of FGF12. We report three individuals from two families with FGF12 duplications. The duplications are flanked and probably mediated by two long interspersed nuclear elements (LINEs). The duplication cases show phenotypic overlap with the cases with intragenic mutations. Though the onset of epilepsy might be later, after the onset of seizures both groups show developmental stagnation and regression in several cases. This illustrates and further confirms that chromosomal FGF12 duplications and intragenic gain-of-function mutations yield overlapping phenotypes.

Keywords: FGF12; LINE; developmental regression; epilepsy; intellectual disability; microduplication 3q28q29.

Figure 1

Graphic presentation of the overlapping gains in band q28q29 of chromosome 3, encompassing FGF12. Schematic representation of chromosome 3 with the 3q28q29 region enlarged in the lower part of the figure (screen shot of the UCSC genome browser build 37/hg19 (http://genome.ucsc.edu/)) with gains detected in individuals 1, 2, and 3 shown as black solid rectangles above the genes in this region. The small vertical bars indicate the probe coverage of the different array platforms, and the blue and red rectangles represent gains and losses, respectively, in the DECIPHER database and the Database of Genomic Variants ¹⁰