Phenytoin-responsive epileptic encephalopathy with a tandem duplication involving
            <i>FGF12</i>

Shi, Rui; Kobayashi, Tomoko; Kikuchi, Atsuo; Sato, Ryo; Uematsu, Mitsugu; An, Kumiko; Kure, Shigeo

doi:10.1212/nxg.0000000000000133

Cited by 15 publications

(31 citation statements)

References 8 publications

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“…In the second category, we identified several interesting candidate genes including a de novo deletion including STAG1 and a de novo intragenic duplication in FGF12 . In both genes, only recently have pathogenic SNVs been reported in patients with neurodevelopmental disorders including epilepsy . We further identified a deletion including SETBP1 associated with Shinzel‐Gieidon syndrome and ID (OMIM 611060) and a duplication including HCN2, a gene in which SNVs exerting a gain‐of‐function effect have recently been suggested as a risk factor for genetic generalized epilepsies .…”

Section: Resultsmentioning

confidence: 91%

“…The patient in this study only showed severe epilepsy and ID, suggesting that the SETBP1 ‐mutation phenotype may be broader than previously described. One patient had a microdeletion, classified here as possibly pathogenic, which includes STAG1 , now linked with epilepsy as a cohesinopathy, and one patient carried a de novo intragenic duplication in FGF12 in which SNVs have recently been reported in patients with epileptic encephalopathies …”

Section: Discussionmentioning

confidence: 99%

“…One patient had a microdeletion, classified here as possibly pathogenic, which includes STAG1, now linked with epilepsy as a cohesinopathy, 24 and one patient carried a de novo intragenic duplication in FGF12 in which SNVs have recently been reported in patients with epileptic encephalopathies. 25 Other interesting candidate genes are highlighted in Table 3 and include HCN2, FMN2, CHRM3, CSNK1G3, and NMT1.…”

Section: Discussionmentioning

confidence: 99%

“…In both genes, only recently have pathogenic SNVs been reported in patients with neurodevelopmental disorders including epilepsy. 24,25 We further identified a deletion including SETBP1 associated with Shinzel-Gieidon syndrome and ID (OMIM 611060) and a duplication including HCN2, a gene in which SNVs exerting a gain-of-function effect have recently been suggested as a risk factor for genetic generalized epilepsies. 26 HCN2 has also previously been associated with febrile epilepsy syndromes; interestingly, the patient carrying this CNV also had a history of febrile seizures.…”

Section: Possibly Pathogenic Cnvsmentioning

confidence: 99%

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Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

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Summary Objective Copy number variations ( CNV s) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNV s to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV . We identified CNV s covering recently reported ( HNRNPU ) or emerging ( RORB ) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNV s, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNV s (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10 −9 ). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNV s. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNV s in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNV s. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Possibly Pathogenic Cnvsmentioning

confidence: 99%

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Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

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“…FGF12 is associated with early infantile epileptic encephalopathy 47 (EIEE47; MIM 617166). Apart from a single patient with gene duplication all 11 reported cases shared the same FGF12 variant (p.Arg114His/c.341G > A) and responded to phenytoin (PHT) and/or phenobarbital (PB) …”

Section: Data Accessibilitymentioning

confidence: 99%

FGF12p.Gly112Ser variant as a cause of phenytoin/phenobarbital responsive epilepsy

Paprocka

Jezela‐Stanek²,

Koppolu

et al. 2019

Clinical Genetics

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Epilepsy phenotype in individuals with chromosomal duplication encompassing FGF12

et al. 2020

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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.

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Phenytoin-responsive epileptic encephalopathy with a tandem duplication involving FGF12

Cited by 15 publications

References 8 publications

Diagnostic implications of genetic copy number variation in epilepsy plus

Diagnostic implications of genetic copy number variation in epilepsy plus

FGF12p.Gly112Ser variant as a cause of phenytoin/phenobarbital responsive epilepsy

Epilepsy phenotype in individuals with chromosomal duplication encompassing FGF12

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