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ARHGEF9 Mutations in Epileptic Encephalopathy/Intellectual Disability: Toward Understanding the Mechanism Underlying Phenotypic Variation

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ARHGEF9 Mutations in Epileptic Encephalopathy/Intellectual Disability: Toward Understanding the Mechanism Underlying Phenotypic Variation Neurogenetics (2018) 19:9–16 https://doi.org/10.1007/s10048-017-0528-2 ORIGINAL ARTICLE ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation Jing-Yang Wang1,2 & Peng Zhou1,2 & Jie Wang1,2 & Bin Tang1,2 & Tao Su 1,2 & Xiao-Rong Liu1,2 & Bing-Mei Li1,2 & Heng Meng3,4 & Yi-Wu Shi 1,2 & Yong-Hong Yi 1,2 & Na He1,2 & Wei-Ping Liao1,2 Received: 7 September 2017 /Accepted: 25 October 2017 /Published online: 13 November 2017 # Springer-Verlag GmbH Germany 2017 Abstract ARHGEF9 resides on Xq11.1 and encodes Missense mutations with severe molecular alteration in the collybistin, which is crucial in gephyrin clustering and DH domain, or located in the DH-gephyrin binding region, GABAA receptor localization. ARHGEF9 mutations have or adjacent to the SH3-NL2 binding site were associated with been identified in patients with heterogeneous phenotypes, severe epilepsy, implying that the clinical severity was poten- including epilepsy of variable severity and intellectual disabil- tially determined by alteration of molecular structure and lo- ity. However, the mechanism underlying phenotype variation cation of mutations. Male patients with ARHGEF9 mutations is unknown. Using next-generation sequencing, we identified presented more severe phenotypes than female patients, which a novel mutation, c.868C > T/p.R290C, which co-segregated suggests a gene-dose effect and supports the pathogenic role with epileptic encephalopathy, and validated its association of ARHGEF9 mutations. This study highlights the role of with epileptic encephalopathy. Further analysis revealed that molecular alteration in phenotype expression and facilitates all ARHGEF9 mutations were associated with intellectual dis- evaluation of the pathogenicity of ARHGEF9 mutations in ability, suggesting its critical role in psychomotor develop- clinical practice. ment. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Keywords ARHGEF9 . Collybistin . Epileptic encephalopathy . Epilepsy . Intellectual disability . Whole Jing-yang Wang and Peng Zhou are co-first authors due to their equal exome sequencing contribution to this work. * Na He [email protected] Introduction * Wei-Ping Liao [email protected] The rho guanine nucleotide exchange factor 9 gene (ARHGEF9, MIM# 300429) encodes collybistin, a member of 1 Institute of Neuroscience and Department of Neurology of the the family of Dbl-like GDP/GTP exchange factors, and is Second Affiliated Hospital of Guangzhou Medical University Please expressed predominantly in the brain. Collybistin plays a critical check if the affiliations are presented correctly.The affiliations are presented correctly., Chang-Gang-Dong Road 250, role in the clustering of gephyrin-dependent glycine receptors γ Guangzhou 510260, China and -aminobutyric acid type A (GABAA) receptors at inhibi- 2 Key Laboratory of Neurogenetics and Channelopathies of tory postsynaptic sites [1]. Deficiency of collybistin due to Guangdong Province and the Ministry of Education of China, knockout of ARHGEF9 in mice induces a region-specific loss Guangzhou 510260, China of gephyrin and GABAA receptors at inhibitory synapses, lead- 3 Department of Neurology, The First Affiliated Hospital of Jinan ing to a significant change in hippocampal synaptic plasticity. University, Guangdong 510630, China Consequently, ARHGEF9-knockout mice exhibited decreased 4 Clinical Neuroscience Institute of Jinan University, exploration in a new environment, increased anxiety-related Guangdong 510630, China response, cognitive aptitude defects, and convulsions [2–4]. 10 Neurogenetics (2018) 19:9–16 In humans, patients with ARHGEF9 defects have been re- used for linkage and segregation analysis. Whole exome ported to present with extensive anomalies, including epilep- sequencing was performed on an Illumina HiSeq 2000 sy, hyperekplexia, intellectual disability, dysmorphism, and sequencer. Paired-end reads with a length of 90 bp were anxiety [5–7]. Mutation of ARHGEF9 was initially discovered generatedbymassiveparallelsequencingwithmorethan in a patient with epileptic encephalopathy (EE) [5]. However, 125 times average depth and more than 98% coverage of later studies identified mutations in patients with other milder the target region, which fulfills the quality criteria. types of epilepsy, and those patients were found to have The raw data were aligned to the reference human genome favorable responses to drug therapies [6, 8, 9]. Several (GRCh37) using Burrows−Wheeler Alignment (BWA). mutations have also been detected in patients with Stepwise filtering was applied to derive potential pathogenic dysmorphism or hyperekplexia without epilepsy [10–12]. variants. First, population-based filtration removed common Recent studies have further identified mutations in patients variants presenting a minor allele frequency (MAF) ≥ 0.005 in with distinct phenotypes of epilepsy or in patients without the 1000 Genomes Project, Exome Aggregation Consortium epilepsy [13, 14]. Therefore, the role of ARHGEF9 in epilep- (ExAC), or ExAC-East Asian Population (ExAC-EAS), ex- sy, particularly in EE, remains elusive. It is unknown whether cept for those previously reported to be associated with dis- phenotype variation correlates with ARHGEF9 mutation ease in the Human Gene Mutation Database (HGMD) and/or genotypes. Online Mendelian Inheritance in Man (OMIM) database. In this study, we performed whole exome sequencing in a Second, functional impact-based filtration prioritized func- family with four male siblings with EE and intellectual tional variants (protein-altering) that are missense, nonsense, disability. A novel mutation in ARHGEF9 was identified indel, frameshift, and splicing variants. Potential pathogenic and co-segregated with EE in this family. We further sys- variants were flagged if predicted as damaging by SIFT tematically reviewed all ARHGEF9 mutations and ana- (http://sift.jcvi.org/), PolyPhen2 (http://genetics.bwh.harvard. lyzed their molecular heterogeneity, aiming to define the edu/pph2/), and Mutation Taster (http://www.mutationtaster. genotype−phenotype correlation and the role of ARHGEF9 org/). Third, inheritance-based filtration filtered variants based mutations in epilepsy and intellectual disability. on family history and possible inheritance models. Sanger sequencing was used to validate the identified potential disease-causing variant. A total of 296 healthy Materials and methods volunteers were recruited as normal controls. Patients Mutation analysis A two-generation family with four affected male siblings To evaluate the pathogenicity of candidate variants, protein was recruited at the Epilepsy Centre of the Second modeling was performed using Iterative Threading Affiliated Hospital of Guangzhou Medical University. ASSEmbly Refinement (I-TASSER) software [18]basedon Clinical data were collected, including age at seizure onset, data from the Protein Data Bank (http://www.rcsb.org). The seizure types and frequency, response to antiepileptic drugs three-dimensional structures were shown using PyMOL 1.7. (AEDs), general and neurological examination results, and To explore the genotype−phenotype association, mutations detailed family history. Brain magnetic resonance imaging of the candidate gene and related phenotypes were systemat- (MRI) was performed to exclude symptomatic epilepsy. ically retrieved on the PubMed database. Video electroencephalography (EEG) was performed, and the results were reviewed by two qualified electroencephalogra- phers. Epileptic seizures and epilepsy were diagnosed and clas- Results sified according to the criteria of the Commission on Classification and Terminology of the International League Mutation screening and clinical features Against Epilepsy (ILAE) [15–17]. This study was approved by the ethics committee of the In the family in this study, four male siblings were affected, hospital, and written informed consent was obtained from the whereas four female siblings and their parents were asymp- patients and their parents. tomatic (Fig.1a). All affected patients showed phenotypic ho- mogeneity in EE and intellectual disability. We performed Whole exome sequencing whole exome sequencing in individual II-7 (proband), II-6, and their father. Sanger sequencing was used to validate the Genomic DNA was extracted from the peripheral blood using positive findings and the variants in II-1, II-8, and their moth- the Qiagen Flexi Gene DNA Kit (Qiagen, Germany). Blood er. We detected three variants that co-segregated with the phe- samples of available parents and siblings were collected and notype in this family. These variants were located in three Neurogenetics (2018) 19:9–16 11 Fig. 1 ARHGEF9 mutation and electroencephalogram (EEG) changes in the proband. a Pedigree of the family with epileptic encephalopathy. Clear symbols represent normal individuals and filled squares represent the affected men. Individuals tested for nucleotide substitution are indicated with either a T (mutant allele) or a C (normal allele). b Sequencing chromatogram for c.868C > T. c The amino acid sequence alignment of collybistin showed that the residue R290 was highly conserved in various species. d Interictal EEG changes in the proband demonstrated generalized and multifocal discharges, including generalized polyspikes (left), focal spike −slow waves in the bilateral temporal lobes (medium), and focal
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