scholarly journals A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study

2020 ◽  
Vol 10 (4) ◽  
pp. 281
Author(s):  
Syuan-Yu Hong ◽  
Jiann-Jou Yang ◽  
Shuan-Yow Li ◽  
Inn-Chi Lee
Keyword(s):  
Pediatric Patients ◽  
Novel Mutation ◽  
Wide Spectrum ◽  
Genetic Disorders ◽  
Neuromuscular Disorders ◽  
Case Series ◽  
Epileptic Encephalopathy ◽  
High Yield ◽  
Whole Exome ◽  
Refractory Seizures

Background: Pediatric epileptic encephalopathy and severe neurological disorders comprise a group of heterogenous diseases. We used whole-exome sequencing (WES) to identify genetic defects in pediatric patients. Methods: Patients with refractory seizures using ≥2 antiepileptic drugs (AEDs) receiving one AED and having neurodevelopmental regression or having severe neurological or neuromuscular disorders with unidentified causes were enrolled, of which 54 patients fulfilled the inclusion criteria, were enrolled, and underwent WES. Results: Genetic diagnoses were confirmed in 24 patients. In the seizure group, KCNQ2, SCN1A, TBCID 24, GRIN1, IRF2BPL, MECP2, OSGEP, PACS1, PIGA, PPP1CB, SMARCA4, SUOX, SZT2, UBE3A, 16p13.11 microdeletion, [4p16.3p16.1(68,345–7,739,782)X1, 17q25.1q25.3(73,608,322–81,041,938)X3], and LAMA2 were identified. In the nonseizure group, SCN2A, SPTBN2, DMD, and FBN1 were identified. Ten novel mutations were identified. The recurrent genes included SCN1A, KCNQ2, and TBCID24. Male pediatric patients had a significantly higher (57% vs. 29%; p < 0.05, odds ratio = 3.18) yield than their female counterparts. Seventeen genes were identified from the seizure groups, of which 82% were rare genetic etiologies for childhood seizure and did not appear recurrently in the case series. Conclusions: Wide genetic variation was identified for severe childhood seizures by WES. WES had a high yield, particularly in male infantile patients.

scholarly journals Genetic epilepsy caused by CDKL5 gene mutations as an example of epileptic encephalopathy and developmental encephalopathy: literature review and own observations

2021 ◽  
Vol 16 (1-2) ◽  
pp. 10-41
Author(s):  
K. Yu. Mukhin ◽  
O. A. Pylaeva ◽  
M. Yu. Bobylova ◽  
V. A. Chadaev
Keyword(s):  
Literature Review ◽  
Genetic Disorders ◽  
Clinical Manifestations ◽  
Case Series ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Serine Threonine Kinase ◽  
Gene Encoding ◽  
Threonine Kinase

The disease caused by mutations in the CDKL5 gene (encoding cyclin-dependent kinase 5, CDK5) belongs to the group of early (infantile) epileptic encephalopathies caused by alterations in the genome. Currently, the disease is called “developmental encephalopathy and epileptic encephalopathy type 2”. This disorder is a complex combination of symptoms that develop due to deficiency or absence of the CDKL5 gene product, which is serine/threonine kinase. The CDKL5 gene is located on X chromosome; the disease has an X-linked dominant inheritance pattern. This literature review summarizes relevant studies analyzing the disease caused by CDKL5 gene mutations, including its genetic and epidemiological aspects, clinical manifestations, characteristics of epilepsy, principles of diagnosis, and therapeutic approaches. We present a case series of several patients with genetic disorders involving the CDKL5 gene.

scholarly journals Clinical and whole-exome sequencing findings in two siblings from Hani ethnic minority with congenital glycosylation disorders

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhen Zhang ◽  
Ti-Long Huang ◽  
Jing Ma ◽  
Wen-Ji He ◽  
Huaiyu Gu
Keyword(s):  
Ethnic Minority ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Chinese Population ◽  
Novel Mutation ◽  
Genetic Disorders ◽  
Central Nervous System Involvement ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Whole Exome

Abstract Background PMM2-CDG, is the most common N-linked glycosylation disorder and subtype among all CDG syndromes, which are a series of genetic disorders involving the synthesis and attachment of glycoproteins and glycolipid glycans. The mutations of PMM2-CDG might lead to the loss of PMM2, which is responsible for the conversion of mannose 6- phosphate into mannose 1-phosphate. Most patients with PMM2-CDG have central nervous system involvement, abnormal coagulation, and hepatopathy. The neurological symptoms of PMM2-CDG are intellectual disability (ID), cerebellar ataxia, and peripheral neuropathy. Now, over 100 new CDG cases have been reported. However, each type of CDG is very rare, and CDGs are problematic to diagnose. In addition, few CDGs have been reported in the Chinese population. Case presentation Here we present a Hani ethnic minority family including two siblings with congenital glycosylation disorders. Whole-exome sequencing revealed compound heterozygous for one novel mutation (c.241–242 del variant) and previously reported mutation (c.395 T > C) in gene of PMM2. Two mutations were found in proband and her sibling by whole-exome sequencing. The mutations were identified in this family by Sanger sequencing and no mutations were detected in the normal control. Conclusions This is the first report to describe mutations in two siblings of Hani ethnic minority which is one of five ethnic groups found only in Yunnan with a population of more than 1 million.

A Novel AMELX Mutation, Its Phenotypic Features, and Skewed X Inactivation

2019 ◽  
Vol 98 (8) ◽  
pp. 870-878 ◽  
Author(s):  
X. Duan ◽  
S. Yang ◽  
H. Zhang ◽  
J. Wu ◽  
Y. Zhang ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Genetic Disorders ◽  
Dental Enamel ◽  
X Inactivation ◽  
Chinese Family ◽  
Reaction Products ◽  
Whole Exome ◽  
Heterozygous Carriers ◽  
Polymerase Chain ◽  
Phenotypic Variations

Amelogenesis imperfecta (AI) is a group of genetic disorders of defective dental enamel. Mutation of AMELX encoding amelogenin on the X chromosome is a major cause of AI. Here we report a Chinese family with hypoplastic and hypomineralized AI. Whole exome analysis revealed a novel mutation c.185delC in exon 5 of AMELX causing the frame shift p.Pro62ArgfsTer47 (or p.Pro62Argfs*47). By sequencing of polymerase chain reaction products and T-vector clones, the mutation was confirmed as homozygous in the proband, hemizygous in her father, and heterozygous in her mother. The proband and her father had small and yellowish teeth with thin and rough enamel that was radiographically indistinguishable from the underlying dentin. Scanning electronic microscopy of 1 maternal tooth showed cracks and exposed loosely packed enamel prisms in affected areas. Consistent with a 25:75 skewing of X inactivation in the peripheral blood DNA as measured by androgen receptor allele methylation, the surface of the mother’s tooth had alternating vertical ridges of transparent normal and white chalky enamel in a 34:66 ratio. In summary, this study provides one of the few phenotypic comparisons of hemizygous and homozygous AMELX mutations and suggests that the skewing of X inactivation in AI contributes to the phenotypic variations in heterozygous carriers of X-linked AI.

scholarly journals Antisense Oligonucleotide Therapy for Neurodevelopmental Disorders

2021 ◽  
pp. 1-6
Author(s):  
Sophie F. Hill ◽  
Miriam H. Meisler
Keyword(s):  
Neurodevelopmental Disorders ◽  
Antisense Oligonucleotides ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Genetic Disorders ◽  
Neuromuscular Disorders ◽  
Epileptic Encephalopathy ◽  
Mrna Splicing ◽  
Patient Specific ◽  
Antisense Oligonucleotide Therapy

Antisense oligonucleotides (ASOs) are short oligonucleotides that can modify gene expression and mRNA splicing in the nervous system. The FDA has approved ASOs for treatment of ten genetic disorders, with many applications currently in the pipeline. We describe the molecular mechanisms of ASO treatment for four neurodevelopmental and neuromuscular disorders. The ASO nusinersen is a general treatment for mutations of <i>SMN1</i> in spinal muscular atrophy that corrects the splicing defect in the <i>SMN2</i> gene. Milasen is a patient-specific ASO that rescues splicing of <i>CNL7</i> in Batten’s disease. STK-001 is an ASO that increases expression of the sodium channel gene <i>SCN1A</i> by exclusion of a poison exon. An ASO that reduces the abundance of the <i>SCN8A</i> mRNA is therapeutic in mouse models of developmental and epileptic encephalopathy. These examples demonstrate the variety of mechanisms and range of applications of ASOs for treatment of neurodevelopmental disorders.

scholarly journals A Novel Non-frameshift ADA Deletion Detected by Whole Exome Sequencing in an Iranian Family with Severe Combined Immunodeficiency

2020 ◽  
Author(s):  
Taravat Talebi ◽  
Alirezai Biglari ◽  
Mohammad Shahroeei ◽  
Majid Changi-Ashtiani ◽  
Hossein Dinmohammadi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Disorders ◽  
Severe Combined Immunodeficiency ◽  
Genetic Diagnosis ◽  
Sample Volume ◽  
Combined Immunodeficiency ◽  
Whole Exome ◽  
And Function

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of genetic disorders caused by early defects in the development and function of T cells. Other lymphocyte lineages (B and/or natural killer cells) are variably affected. With a worldwide frequency of approximately 1:50,000 live births, SCID may result from diverse mutations in over 16 genes. Whole-exome sequencing (WES) provides an opportunity for parallel screening of all those genes. This approach is also useful for genetic diagnosis in parents whose infant expired before genetic testing. Here, we describe a heterozygous novel non-frameshift deletion (c.587_598del p.196_199del) in the adenosine deaminase (ADA) gene identified by WES in healthy parents of an expired child with SCID. The mutation was subsequently confirmed to be homozygous in the deceased baby whose left-over blood sample volume was insufficient for direct WES analysis. In conclusion, we here describe a novel mutation in ADA, a well-known SCID gene.  

scholarly journals Identification of a novel GRIN2D variant in a neonate with intractable epileptic encephalopathy-a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiancheng Jiao ◽  
Li Li ◽  
Min Sun ◽  
Junchen Fang ◽  
Lingzhi Meng ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Case Series ◽  
Respiratory Arrest ◽  
Epileptic Encephalopathy ◽  
Partial Control ◽  
Case Presentation ◽  
Whole Exome ◽  
Novel Variant ◽  
The Central Nervous System ◽  
Spike Wave

Abstract Background N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. The functional NMDA receptors are heterotetramers consisting mainly of two GluN1 and two GluN2 subunits. GluN2 is encoded by the GRIN2D gene. A few case series have shown that GRIN2D variants are linked to developmental and epileptic encephalopathy. In this article, we report a novel GRIN2D variant, namely c.2021C > A (p.T674K) in a neonate with intractable epileptic encephalopathy. Case presentation A 12-day-old boy who had stiffness of the lower and upper extremities since birth was transferred from a local hospital to our department. On admission, the patient presented with head tilting backwards, staring, apnea and hypertonia of limbs. Video electroencephalogram showed continuous, generalized or multi-focal spike-wave and spike-and-slow wave discharges and hypsarrhythmia. A treatment regimen composed of phenobarbital, midazolam, levetiracetam and clonazepam was administered, which however led to only partial control of the seizure. Whole-exome sequencing identified c.2021C > A (p.T674K) in GRIN2D in the patient while such a mutation was not detected in the parents. The patient was hospitalized for 1 month and died of sudden cardio-respiratory arrest 2 weeks after discharge. Conclusions A novel variant of GRIN2D was identified in a neonate with epileptic encephalopathy. Epilepsy associated with this GRIN2D mutation is refractory to conventional anti-epileptic medications.

SCN1A and Its Related Epileptic Phenotypes

2021 ◽  
Author(s):  
Federica Sullo ◽  
Elisa Pasquetti ◽  
Francesca Patanè ◽  
Manuela Lo Bianco ◽  
Simona D. Marino ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Neurological Disorders ◽  
Wide Spectrum ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Behavioral Alterations ◽  
Α Subunit ◽  
Hyperactivity Disorder ◽  
Whole Exome

AbstractEpilepsy is one of the most common neurological disorders, with a lifetime incidence of 1 in 26. Approximately two-thirds of epilepsy has a substantial genetic component in its etiology. As a result, simultaneous screening for mutations in multiple genes and performing whole exome sequencing (WES) are becoming very frequent in the clinical evaluation of children with epilepsy. In this setting, mutations in voltage-gated sodium channel (SCN) α-subunit genes are the most commonly identified cause of epilepsy, with sodium channel genes (i.e., SCN1A, SCN2A, SCN8A) being the most frequently identified causative genes. SCN1A mutations result in a wide spectrum of epilepsy phenotypes ranging from simple febrile seizures to Dravet syndrome, a severe epileptic encephalopathy. In case of mutation of SCN1A, it is also possible to observe behavioral alterations, such as impulsivity, inattentiveness, and distractibility, which can be framed in an attention deficit hyperactivity disorder (ADHD) like phenotype. Despite more than 1,200 SCN1A mutations being reported, it is not possible to assess a clear phenotype–genotype correlations. Treatment remains a challenge and seizure control is often partial and transitory.

scholarly journals New mutations in KCNT2 gene causing early infantile epileptic encephalopathy type 57: Case study and literature review

2020 ◽  
Author(s):  
Meryem Alagoz ◽  
Nasim Kherad ◽  
Sureyya Bozkurt ◽  
Adnan Yuksel
Keyword(s):  
Novel Mutation ◽  
Bioinformatic Analysis ◽  
Epileptic Encephalopathy ◽  
Phenotype Correlation ◽  
Whole Exome ◽  
And Function ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
New Mutations

Purpose. Early infantile epileptic encephalopathy (EIEE) 57 belongs to a group of encephalopathies with early-onset and characterised by severe electroencephalogram abnormalities, seizures, developmental delay and intellectual disability. Method. We carried out Whole Exome analysis using Next Generation Sequencing (NGS) and bioinformatic analysis performed to find mutation associated with the patient phenotypes. The effect of the mutation on protein structure analysed by PolyPhen2 and Swissmodel ExPASy. Results. In this study, we evaluated two unrelated Turkish males diagnosed with EIEE type 57 to investigate the genetic cause of this disease. Whole exome sequencing revealed mutations in KCN2 gene, which is a member of Potassium channels (KCN) gene family associated with epileptic encephalopathies. Two mutations, c.545A>T (p.Asn182Ile and c.2638C>A (p.Leu880Met) were reported here as a novel mutation. Conclusions. Our findings implicate the genotype-phenotype correlation of these mutations. Furthermore, the computational analysis showed their effect on protein binding site and function suggesting their role in the development of early infantile epileptic encephalopathy 57.

scholarly journals Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

2021 ◽  
pp. jmedgenet-2021-107769
Author(s):  
Gökhan Yigit ◽  
Ruth Sheffer ◽  
Muhannad Daana ◽  
Yun Li ◽  
Emrah Kaygusuz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Clinical Symptoms ◽  
Epileptic Encephalopathy ◽  
Specific Form ◽  
Loss Of Function ◽  
Epileptic Encephalopathies ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Heterozygous Carriers ◽  
Refractory Seizures

BackgroundDevelopmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1.MethodsWe performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families.ResultsWe excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE.ConclusionOur finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance.

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