scholarly journals GRIN2A Variants Associated With Idiopathic Generalized Epilepsies

2021 ◽  
Vol 14 ◽  
Author(s):  
Xiao-Rong Liu ◽  
Xing-Xing Xu ◽  
Si-Mei Lin ◽  
Cui-Ying Fan ◽  
Ting-Ting Ye ◽  
...  
Keyword(s):  
Underlying Mechanism ◽  
Epileptic Encephalopathy ◽  
Immunofluorescence Staining ◽  
Absence Seizure ◽  
Incomplete Penetrance ◽  
Missense Mutations ◽  
Gain Of Function ◽  
Quantitative Correlation ◽  
Physiological Alterations ◽  
Whole Exome

Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

scholarly journals Identification of a novel pathogenic missense mutation in PRPF31 using whole exome sequencing: a case report

2018 ◽  
Vol 103 (6) ◽  
pp. 761-767 ◽  
Author(s):  
Laura Bryant ◽  
Olga Lozynska ◽  
Anson Marsh ◽  
Tyler E Papp ◽  
Lucas van Gorder ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Protein Trafficking ◽  
Protein Misfolding ◽  
Autosomal Dominant ◽  
Null Alleles ◽  
Incomplete Penetrance ◽  
Missense Mutations ◽  
Whole Exome

BackgroundVariants in PRPF31, which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in PRPF31 in a family with adRP.MethodsWe performed whole exome sequencing to identify possible pathogenic mutations in the proband of a family with adRP. Available affected family members had a full ophthalmological evaluation including kinetic and two-colour dark adapted static perimetry, electroretinography and multimodal imaging of the retina. Two patients had evaluations covering nearly 20 years. We carried out segregation analysis of the probable mutation, PRPF31 c.590T>C. We evaluated the cellular localisation of the PRPF31 variant (p.Leu197Pro) compared with the wildtype PRPF31 protein.ResultsPRPF31 c.590T>C segregated with the disease in this four-generation autosomal dominant pedigree. There was intrafamilial variability in disease severity. Nyctalopia and mid-peripheral scotomas presented from the second to the fourth decade of life. There was severe rod >cone dysfunction. Visual acuity (VA) was relatively intact and was maintained until later in life, although with marked interocular asymmetries. Laboratory studies showed that the mutant PRPF31 protein (p.Leu197Pro) does not localise to the nucleus, unlike the wildtype PRPF31 protein. Instead, mutant protein resulted in punctate localisation to the cytoplasm.Conclusionsc.590T>C is a novel pathogenic variant in PRPF31 causing adRP with incomplete penetrance. Disease may be due to protein misfolding and associated abnormal protein trafficking to the nucleus.

scholarly journals Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 553 ◽  
Author(s):  
Erika Banuelos ◽  
Keri Ramsey ◽  
Newell Belnap ◽  
Malavika Krishnan ◽  
Chris D. Balak ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Dominant ◽  
Epileptic Encephalopathy ◽  
Myoclonic Epilepsy ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Single Family ◽  
Whole Exome ◽  
Neurological Phenotype ◽  
Syndromic Hearing Loss

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy

scholarly journals Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Gong ◽  
Xianru Jiao ◽  
Dan Yu ◽  
Zhixian Yang
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Ohtahara Syndrome ◽  
Whole Exome

Objective:KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications.Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a ‘change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients.Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.

scholarly journals Novel homozygous mutation in the WWOX gene causes seizures and global developmental delay: Report and review

2018 ◽  
Vol 9 (1) ◽  
pp. 203-208 ◽  
Author(s):  
Salleh N. Ehaideb ◽  
Majed J. Al-Bu Ali ◽  
Jaafer J. Al-obaid ◽  
Kareemah M. Aljassim ◽  
Majid Alfadhel
Keyword(s):  
Developmental Delay ◽  
Fragile Site ◽  
Underlying Mechanism ◽  
Suppressor Gene ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Homozygous Mutation ◽  
Loss Of Function ◽  
Intractable Seizures ◽  
Whole Exome

AbstractTheWWOXgene has a WW domain containing oxidoreductase, which is located at the common fragile site FRA16D at chromosome 16q23.WWOXis a tumor suppressor gene that has been associated with several types of cancer such as hepatic, breast, lung, prostate, gastric, and ovarian. Recently WWOX has been implicated in epilepsy, where studies show homozygous loss-of-function mutation lead to early-infantile epileptic encephalopathy, spinocerebellar ataxia, intractable seizures and developmental delay, and early lethal microcephaly syndrome with epilepsy. Here we investigate two consanguineous Saudi families and we identified three probands with epileptic encephalopathy. Whole exome sequencing revealed a novel homozygous mutation in theWWOXgene in one proband. In addition, we identified a previously reportedWWOXmutation in two probands. Later on these findings were confirmed with Sanger sequencing. The underlying mechanism on how WWOX mutations lead to seizure remains elusive. To date very fewWWOXmutations have been associated with neurological disorder and our newly identified mutations support the notion that WWOX play an important role in neurons and will aid in better diagnosis and genetic counseling.

scholarly journals AB0008 APPLYING WHOLE EXOME SEQUENCING TO FAMILIAL ANTIPHOSPHOLIPID SYNDROME: NEW PLAYERS IN A RARE DISEASE?

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1039.1-1039
Author(s):  
A. Barinotti ◽  
M. Radin ◽  
I. Cecchi ◽  
S. G. Foddai ◽  
E. Rubini ◽  
...  
Keyword(s):  
Immune Response ◽  
Ischemic Stroke ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Antiphospholipid Syndrome ◽  
Missense Mutations ◽  
Literature Research ◽  
Missense Variants ◽  
Vein Thrombosis ◽  
Whole Exome

Background:Antiphospholipid Syndrome (APS) is an autoimmune disease whose precise aetiology is still unknown, but the high heterogeneity of its manifestations and clinical course is presumably due to the occurrence of different mechanisms and alterations at different levels and pathways [1]. The first genetic studies in APS focused primarily on the human leukocytes antigen system region, but more recent data highlighted a role of other genes in APS susceptibility, primarily those involved in the immune response and in the haemostatic process.Objectives:We aimed to deepen the investigation of APS genetic background starting from a case of familial APS, analysing two siblings with thrombotic APS (Table 1), both triple positive for antiphospholipid antibodies (aPL).Table 1.Main clinical and laboratory characteristics of the patients included in the study.PatientAgeaPL ProfileRelevant Clinical History1 (F)51Triple positive (LA, aCL IgG, aβ2GPI IgG)Two episodes of ischemic stroke, one episode of CAPS (renal thrombotic microangiopathy, visual impairment, ischemic stroke)2 (M)47Triple positive (LA, aCL IgG, aβ2GPI IgG)Three episodes of deep vein thrombosis, regardless ongoing well conducted therapy vitamin k antagonist and additional retinal vein thrombosisLA: lupus anticoagulant; aCL: anti-cardiolipin antibodies; aβ2GPI: anti- β2 glycoprotein I antibodies; CAPS: catastrophic APS.Methods:Genomic DNA was extracted from peripheral blood and the samples underwent Whole Exome Sequencing (WES). Sequencing was done on a 100X coverage, and reads have been aligned to the human reference genome (GRCh37/hg19 assembly) using the Burrows–Wheeler Alignment tool (BWA). The mean sequencing depth on target regions was 170X for patient 1, 205X for patient 2, moreover, 99.50% of the targeted bases had at least 10X coverage for all the three donors. The resulting single nucleotide polymorphisms (SNPs) have been analysed through a step-by-step process based on their frequency population (using Genome Aggregation Database), their predicted effects on the protein (using VarSome) and a literature research about the genes carrying them. Moreover, genes previously associated with a pro-thrombotic tendency and with APS have been analysed in the two patients.Results:Starting from more than 120000 SNPs for each patients, the analysis led to reduce the list of SNPs of interest to 27 missense mutations. The complete literature research regarding the genes carrying these mutations allowed to further reduce the number of selected genes, focusing on those that exert a role potentially involved in APS pathogenesis and development. In particular, these genes (PLA2G6, HSPG2, BCL3, ZFAT, ATP2B2, CRTC3 and ADCY3) take part in the immune response and the vascular homeostasis. The list of the DNA missense variants of interest found in our cases of familial APS is resumed in Figure 2.Figure 2.List of DNA missense variants of interest found in patient 1 and 2. Genes potentially involved in APS pathogenesis and development are highlighted in bold.No mutations on genes known to be associated with a pro-thrombotic state (F5, F2, MTHFR, F13A1, PROC, PROS1, FGB and SERPINE1), or on genes previously associated with APS (B2GPI, PF4V1, SELP, TLR2, TLR4, GP Ia, GP1BA, F2R, F2RL1, TFPI, F3, VEGFA, FLT1, and TNF) have been found in the WES analysis.Conclusion:To some extent, this can be seen as a proof of concept of the complexity of APS. Efforts to interpret the genetic risk factors involved in the heterogeneous clinical features of the syndrome, for instance, the integration of WES and network-based approaches might help to identify and stratify patients at risk of developing APS.References:[1]Iuliano A, Galeazzi M, Sebastiani GD. Antiphospholipid syndrome’s genetic and epigenetic aspects. Autoimmun Rev. 2019;18(9).Disclosure of Interests:None declared

scholarly journals Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dongdong Tang ◽  
Yanwei Sha ◽  
Yang Gao ◽  
Jingjing Zhang ◽  
Huiru Cheng ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Sperm Morphology ◽  
Immunofluorescence Staining ◽  
Compound Heterozygous ◽  
Sperm Tail ◽  
Transmission Electron ◽  
Whole Exome ◽  
Detailed Medical History ◽  
Novel Variants ◽  
Common Causes

Abstract Background Asthenozoospermia is one of the most common causes of male infertility, and its genetic etiology is poorly understood. DNAH9 is a core component of outer dynein arms in cilia and flagellum. It was reported that variants of DNAH9 (OMIM: 603330) might cause primary ciliary dyskinesia (PCD). However, variants in DNAH9 lead to nonsyndromic severe asthenozoospermia have yet to be reported. Methods Whole exome sequencing (WES) was performed for two individuals with nonsyndromic severe asthenozoospermia from two non-consanguineous families, and Sanger sequencing was performed to verify the identified variants and parental origins. Sperm routine analysis, sperm vitality rate and sperm morphology analysis were performed according the WHO guidelines 2010 (5th edition). Transmission electron microscopy (TEM, TECNAI-10, 80 kV, Philips, Holland) was used to observe ultrastructures of sperm tail. Quantitative realtime-PCR and immunofluorescence staining were performed to detect the expression of DNAH9-mRNA and location of DNAH9-protein. Furthermore, assisted reproductive procedures were applied. Results By WES and Sanger sequencing, compound heterozygous DNAH9 (NM_001372.4) variants were identified in the two individuals with nonsyndromic severe asthenozoospermia (F1 II-1: c.302dupT, p.Leu101fs*47 / c.6956A > G, p.Asp2319Gly; F2 II-1: c.6294 T > A, p.Phe2098Leu / c.10571 T > A, p.Leu3524Gln). Progressive rates less than 1% with normal sperm morphology rates and normal vitality rates were found in both of the two subjects. No respiratory phenotypes, situs inversus or other malformations were found by detailed medical history, physical examination and lung CT scans etc. Moreover, the expression of DNAH9-mRNA was significantly decreased in sperm from F1 II-1. And expression of DNAH9 is lower in sperm tail by immunofluorescence staining in F1 II-1 compared with normal control. Notably, by intracytoplasmic sperm injection (ICSI), F1 II-1 and his partner successfully achieved clinical pregnancy. Conclusions We identified DNAH9 as a novel pathogenic gene for nonsyndromic severe asthenospermia, and ICSI can contribute to favorable pregnancy outcomes for these patients.

An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ting Xu ◽  
Liang Shi ◽  
Weiqian Dai ◽  
Xuefan Gu ◽  
Yongguo Yu ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Findings ◽  
Recurrent Mutation ◽  
Mrna Splicing ◽  
Additional Patient ◽  
Missense Mutations ◽  
Splicing Variant ◽  
Amino Acid Insertion ◽  
Whole Exome ◽  
Minigene Assay

Abstract Objectives Achondroplasia and hypochondroplasia are the most common forms of disproportionate short stature, of which the vast majority of cases can be attributed to the hotspot missense mutations in the gene FGFR3. Here we presented cases with a novel cryptic splicing variant of FGFR3 gene and aimed to interrogate the variant pathogenicity. Case presentaiton In whole exome sequencing of two patients with hypochondroplasia-like features, a de novo intronic variant c.1075 + 95C>G was identified, predicted to alter mRNA splicing. Minigene assay showed that this intronic variant caused retention of a 90-nucleotide segment of intron 8 in mRNA, resulting in a 30-amino acid insertion at the extracellular domain of the protein. This is the first likely pathogenic splicing variant identified in the FGFR3 gene and was detected in one additional patient among 26 genetically unresolved patients. Conclustions Our results strongly suggest that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing of FGFR3 especially for those patients with equivocal clinical findings and no exonic mutations identified.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

2021 ◽  
Author(s):  
J Fonseca ◽  
C Melo ◽  
C Ferreira ◽  
M Sampaio ◽  
R Sousa ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epileptic Encephalopathy ◽  
Btb Domain ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

scholarly journals PCNT point mutations and familial intracranial aneurysms

Neurology ◽  
2018 ◽  
Vol 91 (23) ◽  
pp. e2170-e2181 ◽  
Author(s):  
Oswaldo Lorenzo-Betancor ◽  
Patrick R. Blackburn ◽  
Emily Edwards ◽  
Rocío Vázquez-do-Campo ◽  
Eric W. Klee ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Intracranial Aneurysms ◽  
Point Mutations ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Interaction Domain ◽  
Knockout Mouse Model ◽  
Whole Exome ◽  
Primordial Dwarfism

ObjectiveTo identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.MethodsWe performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.ResultsWe identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases.ConclusionThe PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt−/−) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

Sign in / Sign up

Export Citation Format

Share Document