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1.
Neurotherapeutics ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34532824

RESUMO

The role of genetics in epilepsy has been recognized for a long time. Over the past decade, genome-wide technologies have identified numerous genes and variants associated with epilepsy. In the clinical setting, a myriad of genetic testing options are available, and a subset of specific genetic diagnoses have management implications. Furthermore, genetic testing can be a dynamic process. As a result, fundamental knowledge about genetics and genomics has become essential for all specialists. Here, we review current knowledge of the genetic contribution to various types of epilepsy, provide an overview of types of genetic variants, and discuss genetic testing options and their diagnostic yield. We also consider advantages and limitations of testing approaches.

3.
Brain ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34415322

RESUMO

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

4.
Dev Med Child Neurol ; 2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34247411

RESUMO

AIM: To determine whether genes that cause developmental and epileptic encephalopathies (DEEs) are more commonly implicated in intellectual disability with epilepsy as a comorbid feature than in intellectual disability only. METHOD: We performed targeted resequencing of 18 genes commonly implicated in DEEs in a cohort of 830 patients with intellectual disability (59% male) and 393 patients with DEEs (52% male). RESULTS: We observed a significant enrichment of pathogenic/likely pathogenic variants in patients with epilepsy and intellectual disability (16 out of 159 in seven genes) compared with intellectual disability only (2 out of 671) (p<1.86×10-10 , odds ratio 37.22, 95% confidence interval 8.60-337.0). INTERPRETATION: We identified seven genes that are more likely to cause epilepsy and intellectual disability than intellectual disability only. Conversely, two genes, GRIN2B and SCN2A, can be implicated in intellectual disability without epilepsy; in these instances intellectual disability is not a secondary consequence of ongoing seizures but rather a primary cause.

5.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
6.
Ann Neurol ; 90(2): 274-284, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34185323

RESUMO

OBJECTIVE: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. METHODS: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. RESULTS: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. INTERPRETATION: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.

7.
Genet Med ; 23(10): 1952-1960, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34113005

RESUMO

PURPOSE: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. METHODS: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. RESULTS: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). CONCLUSION: Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.

8.
Epilepsia Open ; 6(1): 149-159, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33681658

RESUMO

Objectives: Identifying genetic pathogenic variants improves clinical outcomes for children with developmental and epileptic encephalopathy (DEE) by directing therapy and enabling accurate reproductive and prognostic information for families. We aimed to explore the additional personal utility of receiving a genetic diagnosis for families. Methods: Semi-structured interviews were conducted with fifteen families of children with a DEE who had received a genetic diagnosis. The interviews stimulated discussion focusing on the impact of receiving a genetic diagnosis for the family. Interview transcripts were analyzed using the six-step systematic process of interpretative phenomenological analysis (IPA). Results: Three key themes were identified: "Importance of the label," "Relief to end the diagnostic journey," and "Factors that influence personal utility." Families reported that receiving a genetic label improved their knowledge about the likely trajectory of the DEE, increased their hope for the future, and helped them communicate with others. The relief of finally having an answer for the cause of their child's DEE alleviated parental guilt and self-blame as well as helped families to process their grief and move forward. Delay in receipt of a genetic diagnosis diluted its psychological impact. Significance: To date, the factors associated with the personal utility of a genetic diagnosis for DEEs have been under appreciated. This study demonstrates that identifying a genetic diagnosis for a child's DEE can be a psychological turning point for families. A genetic result has the potential to set these families on an adaptive path toward better quality of life through increased understanding, social connection, and support. Early access to genetic testing is important as it not only increases clinical utility, but also increases personal utility with early mitigation of family stress, trauma, and negative experiences.


Assuntos
Síndromes Epilépticas , Predisposição Genética para Doença/genética , Testes Genéticos , Transtornos do Neurodesenvolvimento , Pais/psicologia , Adolescente , Adulto , Encefalopatias , Criança , Pré-Escolar , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Feminino , Humanos , Lactente , Recém-Nascido , Entrevistas como Assunto , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Adulto Jovem
10.
Epilepsia ; 62(2): 325-334, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33410528

RESUMO

OBJECTIVE: Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. METHODS: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. RESULTS: The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one-half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one-third of all cases paroxysms of fast activity with electrodecrement. ALG13-related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one-third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. SIGNIFICANCE: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.


Assuntos
Deficiências do Desenvolvimento/fisiopatologia , Epilepsia Resistente a Medicamentos/fisiopatologia , N-Acetilglucosaminiltransferases/genética , Espasmos Infantis/fisiopatologia , Hormônio Adrenocorticotrópico/uso terapêutico , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Dieta Cetogênica , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/terapia , Discinesias/genética , Discinesias/fisiopatologia , Eletroencefalografia , Síndromes Epilépticas/genética , Síndromes Epilépticas/fisiopatologia , Síndromes Epilépticas/terapia , Feminino , Glucocorticoides/uso terapêutico , Hormônios/uso terapêutico , Humanos , Lactente , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Fenótipo , Comportamento Social , Espasmos Infantis/genética
11.
Epilepsia ; 62(2): 358-370, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33475165

RESUMO

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.


Assuntos
Deficiências do Desenvolvimento/epidemiologia , Epilepsias Mioclônicas/epidemiologia , Espasmos Infantis/epidemiologia , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/fisiopatologia , Progressão da Doença , Eletroencefalografia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/fisiopatologia , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/epidemiologia , Síndromes Epilépticas/etiologia , Síndromes Epilépticas/fisiopatologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Síndrome de Lennox-Gastaut/tratamento farmacológico , Síndrome de Lennox-Gastaut/epidemiologia , Síndrome de Lennox-Gastaut/etiologia , Síndrome de Lennox-Gastaut/fisiopatologia , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/epidemiologia , Malformações do Desenvolvimento Cortical/cirurgia , Mortalidade , Índice de Gravidade de Doença , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/etiologia , Espasmos Infantis/fisiopatologia , Vitória/epidemiologia
12.
Epilepsia ; 62(1): e13-e21, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33280099

RESUMO

Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.


Assuntos
Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Epilepsias Mioclônicas Progressivas/genética , Proteínas Ligases SKP Culina F-Box/genética , Espasmos Infantis/genética , Adolescente , Adulto , Encefalopatias/complicações , Encefalopatias/genética , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Códon sem Sentido , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/fisiopatologia , Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia , Síndromes Epilépticas/complicações , Síndromes Epilépticas/genética , Síndromes Epilépticas/fisiopatologia , Feminino , Mutação da Fase de Leitura , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto , Epilepsias Mioclônicas Progressivas/complicações , Epilepsias Mioclônicas Progressivas/fisiopatologia , Fenótipo , Espasmos Infantis/complicações , Espasmos Infantis/fisiopatologia , Adulto Jovem
13.
Genet Med ; 23(4): 653-660, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33299146

RESUMO

PURPOSE: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals. METHODS: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed. RESULTS: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex. CONCLUSION: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."


Assuntos
Encefalopatias , Epilepsia , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Proteína 25 Associada a Sinaptossoma/genética , Pré-Escolar , Epilepsia/genética , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo
14.
Mol Genet Genomic Med ; 9(1): e1542, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33350591

RESUMO

BACKGROUND: CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. METHODS: We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. RESULTS: Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. CONCLUSIONS: Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.


Assuntos
Deficiências do Desenvolvimento/genética , Vitreorretinopatias Exsudativas Familiares/genética , beta Catenina/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Vitreorretinopatias Exsudativas Familiares/patologia , Feminino , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Fenótipo , Retina/patologia
15.
Epilepsia ; 61(11): 2461-2473, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32954514

RESUMO

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.


Assuntos
Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Variação Genética/genética , Canais de Potássio Shab/genética , Adolescente , Adulto , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia/tendências , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
Curr Opin Genet Dev ; 65: 98-102, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32615329

RESUMO

Poison exons are naturally occurring, highly conserved alternative exons that contain a premature termination codon. Inclusion of a poison exon in a transcript targets the transcript for nonsense mediated decay, decreasing the amount of protein produced. Poison exons are proposed to play an important role in tissue-specific expression, development and autoregulation of gene expression. Recently, several studies that performed systematic investigations of alternative splicing in the brain have highlighted the abundance of transcripts containing poison exons, some of which are spliced in a cell type-specific manner. Pathogenic variants in or near poison exons that result in aberrant splicing have been identified in several genes including FLNA, SCN1A and SNRPB. Improved understanding of the role of poison exons in development and disease may present opportunities to solve previously undiagnosed disease and to develop therapeutic approaches in the future.

17.
J Pediatr ; 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32553838

RESUMO

OBJECTIVES: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population. STUDY DESIGN: We implemented a process to provide clinical-grade rES to eligible children at a single institution. Eligibility included (a) recommendation of rES by a consulting geneticist, (b) monogenic disorder suspected, (c) rapid diagnosis predicted to affect inpatient management, (d) pretest counseling provided by an appropriate provider, and (e) unanimous approval by a committee of 4 geneticists. Trio exome sequencing was sent to a reference laboratory that provided verbal report within 7-10 days. Clinical outcomes related to rES were prospectively collected. Input from geneticists, genetic counselors, pathologists, neonatologists, and critical care pediatricians was collected to identify changes in management related to rES. RESULTS: There were 54 patients who were eligible for rES over a 34-month study period. Of these patients, 46 underwent rES, 24 of whom (52%) had at least 1 change in management related to rES. In 20 patients (43%), a molecular diagnosis was achieved, demonstrating that nondiagnostic exomes could change medical management in some cases. Overall, 84% of patients were under 1 month old at rES request and the mean turnaround time was 9 days. CONCLUSIONS: rES testing has a significant impact on the management of critically ill children with suspected monogenic disease and should be considered standard of care for tertiary institutions who can provide coordinated genetics expertise.

18.
Am J Hum Genet ; 106(5): 623-631, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32275884

RESUMO

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.


Assuntos
Alelos , Encéfalo/anormalidades , Proteínas de Drosophila/genética , Anormalidades do Olho/genética , Cardiopatias Congênitas/genética , Mutação com Perda de Função/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Transporte Ativo do Núcleo Celular , Animais , Núcleo Celular/metabolismo , Pré-Escolar , Dendritos/metabolismo , Dendritos/patologia , Drosophila melanogaster , Anormalidades do Olho/mortalidade , Feminino , Fibroblastos , Genes Recessivos , Cardiopatias Congênitas/mortalidade , Humanos , Lactente , Recém-Nascido , Judeus/genética , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/deficiência , Convulsões/metabolismo , Síndrome , beta Carioferinas/metabolismo
19.
Epilepsy Curr ; 20(2): 88-89, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32313504
20.
F1000Res ; 92020.
Artigo em Inglês | MEDLINE | ID: mdl-32201576

RESUMO

Developmental and epileptic encephalopathies (DEEs) are a group of severe, early onset epilepsies characterized by refractory seizures, developmental delay or regression associated with ongoing epileptic activity, and generally poor prognosis. DEE is genetically and phenotypically heterogeneous, and there is a plethora of genetic testing options to investigate the rapidly growing list of epilepsy genes. However, more than 50% of patients with DEE remain without a genetic diagnosis despite state-of-the-art genetic testing. In this review, we discuss the major advances in epilepsy genomics that have surfaced in recent years. The goal of this review is to reach a larger audience and build a better understanding of pathogenesis and genetic testing options in DEE.


Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Testes Genéticos , Genômica , Humanos
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