Abstract
Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2–3 years and intellectual disability. Three developed afebrile seizures between age 7–17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.
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Acknowledgements
We thank the family for participation in our study. The study was supported by the Deutsche Forschungsgemeinschaft with a Trilateral Grant (HE 5415/5-1) and within the EuroEPINOMICS project (HE 5415/3-1), the Christian-Albrechts-University Kiel, the Detlev-Wrobel-Fonds for Epilepsy Research Frankfurt, the Klaus-Dieter Scharf-Forschungsprojekt and the Share Value Stiftung.
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The study was approved by the Sheba Medical Center Helsinki Committee and the ethics committee of the University of Kiel and has, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants or their legal guardians provided written informed consent.
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Klein, K.M., Pendziwiat, M., Eilam, A. et al. The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures. J Neurol 264, 1421–1425 (2017). https://doi.org/10.1007/s00415-017-8539-3
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DOI: https://doi.org/10.1007/s00415-017-8539-3