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. K E Y W O R D S developmental regression, epilepsy, FGF12, intellectual disability, LINE, microduplication 3q28q29 302 | WILLEMSEN Et aL.

Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 associated with Developmental and Epileptic Encephalopathy and Autism Spectrum Disorder

“…The only difference between the point mutations and the CNVs was the age of onset, with later onset in the duplication cases at a median age of onset of 15.5 months (n = 4). 19,23 This finding is in line with previous studies, where Na V 1.2 LOF variants were shown to be associated with a later disease onset. 25 In summary, the missense variant G50S/G112S led to a clear GOF effect on both channels, while both duplications were associated with LOF effects.…”

“…089-192.451.114), which was found in one individual, and the duplication 3q28q29 (chr3:191876978-192454675), which was identified in two related individuals, have been published previously within a clinical report. 19 To analyse the transcript of the first duplication, we performed RNA purification from fibroblasts and retrotranscription to cDNA, using the Isolation II RNA Mini kit (Bioline) and the First strand cDNA synthesis kit for RT-PCR (Roche), respectively, according to manufacturer protocols.…”

“…In addition to the above-mentioned patients and variants, we included three different copy number variants (CNVs) (3q28q29 (191,876,454,675) X3; 3q28q29 (191,876,,454,685) X3; 3q28q29(191,860,089-192,451,114) X3) which have been published before. 19,23 The first duplication was already characterized on a molecular level 23 while the other two duplications were not further characterized. None of them had been functionally analysed.…”

The FGF/FGFR system in the microglial neuroinflammation with Borrelia burgdorferi: intersectionality with other neurological conditions

“…FGF12 gene expression has been shown to be induced in BV2 microglia in response to LPS [51], however no role for it has been described until this study. The main focus of FGF12 studies has been with its genetic alterations and associated epileptic changes through its ability to bind voltage-gated sodium ion channels [52, 53]. Its expression has also been shown to be elevated in anterior cingulate cortex of patients with major depressive disorder (MDD) [54].…”

Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series

“…The duplication 3q28q29(chr3:191.860.089-192.451.114), which was found in one individual, and the duplication 3q28q29 (chr3:191876978-192454675), which was identified in two related individuals, have been published previously within a clinical report. 19 To analyse the transcript of the first duplication, we performed RNA purification from fibroblasts and retrotranscription to cDNA, using the Isolation II RNA Mini kit (Bioline) and the First strand cDNA synthesis kit for RT-PCR (Roche), respectively, according to manufacturer protocols. For the CNV-specific PCR, the following primers were used: FGF12For7: CTC TCT TCA ATC TAA TTC CCG TGG and FGF12Rev8: GTA GTC GCT GTT TTC GTC CTT GGT C. For the analysis of the second duplication, RNA from venous blood of both patients was isolated and retro-transcribed in cDNA followed by a CNV-specific PCR using the following primers: FGF12For7: CTC TCT TCA ATC TAA TTC CCG TGG and FGF12Rev3: CCT TGT CAC AAT CCC TTT GAG CTG G. All three PCR products were sent for sequencing to LGC Genomics GmbH (Berlin, Germany).…”