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1.
Brain ; 142(11): 3367-3374, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31608932

RESUMO

Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g. epilepsy, intellectual disability, motor dysfunction). Most cases have a supposed environmental clastic vascular or infectious origin but progress in genomics has revealed new monogenic entities. We report four cases from two independent families sharing a common recognizable lethal syndromic polymicrogyria of autosomal recessive inheritance. Beyond diffuse polymicrogyria detected prenatally, pathological examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. In all affected cases, exome sequencing showed a pathogenic homozygous nonsense ATP1A2 variant. This resulted in absence of immunodetectable ATP1A2 protein in two brains analysed. ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290). Through the description of this genetic entity, we emphasize the possibility of dual mode of transmission for disease-causing genes and provide the key neuropathological features that should prompt geneticists to test for mutations in the ATP1A2 gene.

2.
Prenat Diagn ; 39(11): 1026-1034, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31299102

RESUMO

OBJECTIVE: Neural tube defects (NTDs) are one of the most common congenital anomalies caused by a complex interaction of many genetic and environmental factors. In about 10% of cases, NTDs are associated with genetic syndromes or chromosomal anomalies. Among these, SOX3 duplication has been reported in some isolated cases. The phenotype associated with this microduplication is variable and includes myelomeningocele (MMC) in both sexes as well as hypopituitarism and cognitive impairment in males. In order to determine the prevalence of this anomaly in fetuses with MMC, a retrospective cohort of fetuses with MMC was analyzed by quantitative PCR (qPCR) targeting SOX3 locus. METHODS: The detection of an SOX3 microduplication by chromosomal microarray analysis (CMA) in two female fetuses with MMC prompted us to analyze retrospectively by qPCR this gene in a cohort of 53 fetuses with MMC. RESULTS: In addition to our two initial cases, one fetus harboring an Xq27.1q28 duplication that encompasses the SOX3 gene was detected. CONCLUSION: Our data demonstrate that SOX3 duplication is a genomic imbalance involved in the pathogenesis of NTDs. In addition, our survey highlights the importance of CMA testing in fetuses with NTDs to enable genetic counseling upstream of any considerations of in utero fetal surgery.

3.
Hum Mutat ; 40(11): 1993-2000, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31230393

RESUMO

Human retrocopies, that is messenger RNA transcripts benefitting from the long interspersed element 1 machinery for retrotransposition, may have specific consequences for genomic testing. Next genetration sequencing (NGS) techniques allow the detection of such mobile elements but they may be misinterpreted as genomic duplications or be totally overlooked. We report eight observations of retrocopies detected during diagnostic NGS analyses of targeted gene panels, exome, or genome sequencing. For seven cases, while an exons-only copy number gain was called, read alignment inspection revealed a depth of coverage shift at every exon-intron junction where indels were also systematically called. Moreover, aberrant chimeric read pairs spanned entire introns or were paired with another locus for terminal exons. The 8th retrocopy was present in the reference genome and thus showed a normal NGS profile. We emphasize the existence of retrocopies and strategies to accurately detect them at a glance during genetic testing and discuss pitfalls for genetic testing.

4.
Orphanet J Rare Dis ; 14(1): 121, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151468

RESUMO

Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as "overfriendliness" and "hyersociability". WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic.Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin.The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in "typical" WBS patients: therefore, the terms "overfriendliness" and "hypersociability" appear to be a misleading oversimplification.The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit.

6.
J Thromb Haemost ; 17(7): 1097-1103, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31021037

RESUMO

Essentials No F8 genetic abnormality is detected in about 2% of severe hemophilia A patients. Detection of F8 structural variants remains a challenge. We identified a new F8 rearrangement in a severe hemophilia A patient using nanopore sequencing. We highlight the value of single-molecule long-read sequencing technologies in a genomics laboratory. BACKGROUND: No F8 genetic abnormality is detected in about 2% of severe hemophilia A patients using conventional genetic approaches. In these patients, deep intronic variation or F8 disrupting genomic rearrangement could be causal. OBJECTIVE: To characterize, in a genetically unresolved severe hemophilia A patient, a new Xq28 rearrangement disrupting F8 using comprehensive molecular techniques including nanopore sequencing. RESULTS: Long-range polymerase chain reaction (PCR) performed throughout F8 identified a nonamplifiable region in intron 25 indicating the presence of a genomic rearrangement. F8 messanger ribonucleic acid (mRNA) analysis including 3'rapid amplification of complementary deoxyribonucleic acid (cDNA) ends and nanopore sequencing found the presence of a F8 fusion transcript in which F8 exon 26 was replaced by a 742-bp pseudoexon corresponding to a noncoding region located at the beginning of the long arm of chromosome X (Xq12; chrX: 66 310 352-66 311 093, GRCh37/hg19). Cytogenetic microarray analysis found the presence of a Xq11.1q12 gain of 3.8 Mb. The PCR amplification of junction fragments and fluorescent in situ hybridization (FISH) analysis found that the Xq11q12 duplicated region was inserted in the F8 intron 25 genomic region. CONCLUSION: We characterized a novel genomic rearrangement in which a 3.8-Mb Xq11.1q12 gain inserted in the F8 intron 25 led to an aberrant fusion transcript in a patient with severe hemophilia A (HA), using comprehensive molecular techniques. This study highlights the value of single-molecule long-read sequencing technologies for molecular diagnosis of HA especially when conventional genetic approaches have failed.

7.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

8.
Neurology ; 92(11): e1238-e1249, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30737342

RESUMO

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

9.
Eur J Med Genet ; 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30389587

RESUMO

Hereditary hemorrhagic telangiectasia is usually linked to the presence of a pathogenic mutation ACVRL1 or ENG. Thus, apparently there is no benefit to perform an array CGH in case of HHT. However, ENG has been involved in a contiguous gene syndrome due to a de novo 9q33.3q34.11 microdeletion. We describe here a new contiguous gene syndrome involving ACVRL1 gene. A 50-year-old female patient had a typical clinical presentation of hereditary hemorrhagic telangiectasia (HHT) with epistaxis, cutaneous-mucous telangiectases, arteriovenous malformation. She also presented a cognitive disability. Cognitive assessment showed a heterogeneous cognitive disorder predominating in the executive sphere without intellectual deficiency. She had no peculiar morphological feature. Neurological examination disclosed the presence of contralateral mirror movements during voluntary movement of each hand. A heterozygous deletion of the whole ACVRL1 gene (exons 1 to 10) was found to be responsible for the HHT features. To investigate further the dysexecutive syndrome and the mirror movements, we performed oligonucleotide array comparative genomic hybridization (array CGH) study (180K, Agilent, Santa-Clara, CA, USA). This study revealed a de novo 1.58 Mb deletion on chromosome 12q13.12q13.13 encompassing the ACVRL1 and SCN8A genes. To our knowledge, this deletion has not been previously reported and defines a new contiguous gene syndrome. The loss of one ACVRL1 allele is likely to be responsible for the HHT phenotype, while the deletion of the SCN8A gene is likely to be the cause of the mild cognitive disorder. SCN8A haploinsufficiency might also be involved in the occurrence of mirror movements. This report highlights the benefit of searching for large rearrangements in cases including unusual symptoms in association with HHT. On the other hand, an early diagnosis of 12q13.12q13.13 microdeletion based on the presence of a dysexecutive syndrome and/or mirror movement may allow to prevent HHT complications.

11.
Artigo em Inglês | MEDLINE | ID: mdl-30191619

RESUMO

OBJECTIVES: To validate and evaluate an integrated protocol for non-invasive prenatal genetic screening (NIPS) for common fetal aneuploidies in a clinical setting, using the semiconductor sequencing technology, Ion Proton. METHODS: This prospective cohort study included 2505 pregnant women from seven academic genetic laboratories (695 high risk pregnancies in a validation study and 1810 pregnancies with a risk higher than 1/250 without ultrasound anomalies, in a real NIPS clinical setting). Cell free DNA from plasma samples was sequenced using Ion Proton sequencer, and sequencing data were analyzed using the open-access software WISECONDOR. Performance metrics for detection of trisomies 21, 18 and 13, were calculated based on either fetal karyotype result or clinical data collected at birth. We also evaluated the failure rate and compared three methods of fetal fraction quantification (RASSF1A assay, DEFRAG and SANEFALCON software). RESULTS: Sensitivities and specificities were: 98.3% (95%CI: 93.5 - 99.7) and 99.9% (95%CI: 99.4 - 100) for T21, 96.7% (95%CI: 80.9 - 99.8) and 100% (95%CI: 99.6 - 100) for T18, 94.1% (95%CI: 69.2 - 99.7) and 100% (95%CI: 99.6 - 100) for T13. Our failure rate was 1.2% at first and as low as 0.6% after re-testing some of the failed samples. Fetal fraction estimation by RASSF1A assay was consistent with DEFRAG results, both of which are adequate for routine diagnosis. CONCLUSIONS: We describe one of the largest studies evaluating the Ion Proton based NIPS and the first clinical study reporting pregnancy outcome in a large set of patients. We demonstrate that this platform is highly efficient in detecting the three most common trisomies. Our protocol is robust and can be easily implemented in any medical genetics laboratory. This article is protected by copyright. All rights reserved.

12.
Epileptic Disord ; 20(4): 289-294, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078772

RESUMO

SCN8A encephalopathy is a newly defined epileptic encephalopathy caused by de novo mutations of the SCN8A gene. We report herein a four-year-old boy presenting with severe non-epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novo heterozygous missense mutation of SCN8A. This case shows that paroxysmal non-epileptic episodes of severe tremor and hyperekplexia-like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences on www.epilepticdisorders.com].


Assuntos
Encefalopatias , Epilepsia , Hiperecplexia , Doenças do Recém-Nascido , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Tremor , Encefalopatias/diagnóstico , Encefalopatias/genética , Encefalopatias/fisiopatologia , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/fisiopatologia , Humanos , Hiperecplexia/diagnóstico , Hiperecplexia/genética , Hiperecplexia/fisiopatologia , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/fisiopatologia , Masculino , Tremor/diagnóstico , Tremor/genética , Tremor/fisiopatologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-30126759

RESUMO

Christianson syndrome (CS) is a X-linked neurodevelopmental disorder, including severe intellectual disability (ID), progressive microcephaly, ataxia, autistic behaviour (ASD), near absent speech, and epilepsy. Electrical status epilepticus in sleep (ESES) has been reported in two patients. We describe five male patients from three unrelated families with Christianson syndrome caused by a pathogenic nucleotide variation or a copy-number variation involving SLC9A6. ESES was present in three out of the five patients in the critical age window between 4 and 8 years. All patients presented with severe intellectual disability, autistic features, and hyperactivity. Epilepsy onset occurred within the first two years of life. Seizures were of various types. In the two boys with a 20-years follow-up, epilepsy was drug-resistant during childhood, and became less active in early adolescence. Psychomotor regression was noted in two patients presenting with ESES. It was difficult to assess to what extent ESES could have contributed to the pathophysiological process, leading to regression of the already very limited communication skills. The two published case reports and our observation suggests that ESES could be a constitutive feature of Christianson syndrome, as it has already been shown for other Mendelian epileptic disorders, such as GRIN2A and CNKSR2-related developmental epileptic encephalopathies. Sleep EEG should be performed in patients with Christianson syndrome between 4 and 8 years of age. ESES occurring in the context of ID, ASD and severe speech delay, could be helpful to make a diagnosis of CS.

15.
Am J Hum Genet ; 102(5): 995-1007, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656858

RESUMO

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

16.
Ann Neurol ; 83(5): 926-934, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29630738

RESUMO

OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.

17.
J Autism Dev Disord ; 48(8): 2886-2889, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29589274

RESUMO

The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.

18.
Mol Syndromol ; 8(6): 325-330, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29230163

RESUMO

We report a 3-generation family in which 2 Xp copy number variations (CNVs) co-segregate. The proband presented with syndromic intellectual disability. The CNV had been revealed by conventional karyotyping, identifying a large Xp22 duplication causing an Xp functional disomy. Family studies found that this duplication was inherited from the proband's mother and was also present in one of his sisters. This sister had conventional karyotyping performed during pregnancy with a normal result. Postnatally, her child, the proband's nephew, presented with autism spectrum disorders. aCGH revealed a 339-kb IL1RAPL1 duplication. Overall, the proband, his mother, and one of his sisters all harboured both CNVs, while his other sister and the 2 sons of each sister only carried the IL1RAPL1 intragenic duplication. As seen in this family, we emphasise the importance of small CNV detection, the pathogenicity of IL1RAPL1 exonic duplications in male carriers, and the difficulties for genetic counselling with the risk of double diagnosis in a single patient.

19.
Eur J Hum Genet ; 25(3): 376-380, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28051072

RESUMO

We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1. Massive parallel sequencing was performed using a gene panel including 450 genes related to intellectual disability and autism spectrum disorders. We found a homozygous missense variation of GRIN1 (c.679G>C; p.(Asp227His)) in the two affected sibs, which was inherited from both unaffected heterozygous parents. Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders. The p.(Asp227His) variant is located in the same aminoterminal protein domain as the recently published p.(Arg217Trp), which was found at the homozygous state in two patients with a similar phenotype of severe intellectual disability and autistic features but without epilepsy. In silico predictions were consistent with a deleterious effect. The present findings further expand the clinical spectrum of GRIN1 variants and support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance.


Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Consanguinidade , Feminino , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Irmãos , Síndrome
20.
Neurology ; 88(5): 483-492, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28053010

RESUMO

OBJECTIVE: To examine the role of mutations in GABRB3 encoding the ß3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. RESULTS: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant ß3, together with α5 and γ2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. CONCLUSIONS: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.


Assuntos
Epilepsia/genética , Mutação , Receptores de GABA-A/genética , Animais , Automação Laboratorial , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Potenciais da Membrana/fisiologia , Oócitos , Técnicas de Patch-Clamp , Fenótipo , Receptores de GABA-A/metabolismo , Xenopus laevis
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