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1.
Proc Natl Acad Sci U S A ; 116(9): 3662-3667, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808755

RESUMO

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b -/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b -/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b -/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b -/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.


Assuntos
Anormalidades do Olho/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Animais , Encéfalo/fisiopatologia , Criança , Anormalidades do Olho/fisiopatologia , Facies , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Microcefalia/fisiopatologia , Mutação , Fenótipo , Ubiquitina/genética
2.
Psychiatry Res ; 271: 590-597, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30554107

RESUMO

The FOXP2 gene is hypothesised to be involved in schizophrenia by affecting speech and language development. Associations between common single nucleotide polymorphisms (SNPs) in FOXP2 and language have been inconsistent. We tested five previously associated SNPs for association with language in the Western Australian Family Study of Schizophrenia (n = 709, including n = 333 with schizophrenia/spectrum disorder) and found no significant associations. When we included all common FOXP2 variants, one SNP (rs2189008) was nominally associated with language. This is the most comprehensive analysis to date and indicates that common variants in FOXP2 do not play a major role in speech and language development in a clinical family sample.


Assuntos
Fatores de Transcrição Forkhead/genética , Transtornos do Desenvolvimento da Linguagem/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/complicações , Masculino , Pessoa de Meia-Idade , Esquizofrenia/complicações , Fala/fisiologia , Adulto Jovem
3.
Am J Hum Genet ; 103(6): 1045-1052, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30526862

RESUMO

We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗20), c.1348C>T (p.Arg450∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.


Assuntos
Agressão/fisiologia , Nanismo/genética , Variação Genética/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Microcefalia/genética , Adolescente , Animais , Criança , Drosophila melanogaster/genética , Éxons/genética , Feminino , Técnicas de Inativação de Genes/métodos , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , RNA Mensageiro/genética , RNA de Transferência/genética
4.
J Genet ; 97(5): 1485-1491, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30555099

RESUMO

Genetic variation of language genes affect neurophysiology of brain and can thus influence the way people respond to environmental language input, leading to differences in terms of their response to environmental language learning. Conversely, language learning environment too can affect gene expressions through neuroepigenetic mechanisms, leading to increasedinterindividual differences. Further, language-related cognitive processes such as learning, working memory and perception; and language-related affective factors such as stress and positive emotion involve neuroplasticity, which is also epigenetically regulated. Language intervention methods must understand the extent and the type of difficulties, and must offer personalized learning andmedical solutions. Medical intervention in terms of epigenetics and neurotransmitter regulation is proposed in addition to effectiveteaching methods to aid in effective language acquisition.


Assuntos
Predisposição Genética para Doença/genética , Transtornos do Desenvolvimento da Linguagem/genética , Linguagem , Aprendizagem/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Cognição/fisiologia , Humanos , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Memória de Curto Prazo/fisiologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Polimorfismo de Nucleotídeo Único
5.
Semin Pediatr Neurol ; 26: 25-27, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29961511

RESUMO

Recent technological advances in exome sequencing or targeted gene sequencing with epilepsy panels have allowed clinicians to better understand the pathogenesis and clinical presentation of children with epilepsy. We present a child with a SLC6A1 mutation with language delay and autistic spectrum disorder and remind the reader that the identification of specific mutations in these conditions increase the likelihood of identification of potential therapeutic targets.


Assuntos
Epilepsia/genética , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Pré-Escolar , Diagnóstico Diferencial , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/diagnóstico por imagem , Transtornos do Desenvolvimento da Linguagem/tratamento farmacológico , Transtornos do Desenvolvimento da Linguagem/fisiopatologia
6.
Epilepsia ; 59(2): 389-402, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29315614

RESUMO

OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects. RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg). SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.


Assuntos
Epilepsias Mioclônicas/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/complicações , Ataxia/genética , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Epilepsias Parciais/complicações , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Resultado do Tratamento , Ácido Valproico/uso terapêutico , Adulto Jovem
7.
Brain Dev ; 40(1): 36-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28774669

RESUMO

PURPOSE: To clarify the relationship between macrocephaly and neurodevelopmental disorders, as well as identify the prevalence of PTEN mutations in autism spectrum disorders with macrocephaly in Japan. SUBJECTS AND METHODS: Diagnostic and other medical information of children with macrocephaly younger than 4years (n=93) were collected for analysis. PTEN gene mutation analysis was conducted in another set of 16 macrocephalic individuals aged 3-22years. RESULTS: Sixteen macrocephalic children were associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) (n=6), autistic traits (n=5), intellectual disability (n=5), attention deficit hyperactivity disorder (n=1), developmental coordination disorders (n=1), and language disorder (n=1). Male gender was significantly linked to these disorders, whereas a family history and degree of macrocephaly were not significantly linked to the diagnosis. A novel mutation in the PTEN gene was identified in a 16-year-old girl with autism, mental retardation, language delay, extreme macrocephaly (+4.7SD) with a prominent forehead, and digital minor anomalies. CONCLUSION: Children with macrocephaly, particularly males, are at a higher risk of neurodevelopmental disorders, rather than progressive etiologies, such as hydrocephalus and neurodegenerative disorders. The data provide a basis for routine health checks for young children in Japan, including the follow-up management and possible screening of PTEN mutations in children with ASDs and macrocephaly.


Assuntos
Transtorno do Espectro Autista/genética , Megalencefalia/genética , PTEN Fosfo-Hidrolase/genética , Transtorno do Espectro Autista/fisiopatologia , Transtorno Autístico/genética , Pré-Escolar , Anormalidades Craniofaciais , Estudos Transversais , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Japão , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Transtornos das Habilidades Motoras , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , PTEN Fosfo-Hidrolase/metabolismo , Prevalência
8.
Epileptic Disord ; 19(4): 450-455, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29258966

RESUMO

Somatic mutation of the lissencephaly-1 gene is a cause of subcortical band heterotopia ("double cortex"). The severity of the phenotype depends on the level of mutation in brain tissue. Detecting and quantifying low-level somatic mosaic mutations is challenging. Here, we utilized droplet digital PCR, a sensitive method to detect low-level mutation. Droplet digital PCR was used in concert with classic genotyping techniques (SNaPshot assays and pyrosequencing) to detect and characterize the tissue mosaicism of a somatic mutation (LIS1 c.190A>T; p.K64X) in a patient with posterior bilateral SBH and refractory epilepsy. The high sensitivity of droplet digital PCR and the ability to target individual DNA molecules allowed us to detect the mutation at low level in the brain, despite the low quality of the DNA sample derived from formalin-fixed paraffin-embedded tissue. This low mutation frequency in the brain was consistent with the relatively subtle malformation resolved by magnetic resonance imaging. The presence of the mutation in other tissues from the patient permitted us to predict the timing of mutagenesis. This sensitive methodology will have utility for a variety of other brain malformation syndromes associated with epilepsy for which historical pathological specimens are available and specific somatic mosaic mutations are predicted.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Epilepsia Resistente a Medicamentos/genética , Epilepsias Parciais/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Adulto , Feminino , Humanos , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Reação em Cadeia da Polimerase em Tempo Real
9.
Artigo em Inglês | MEDLINE | ID: mdl-28963436

RESUMO

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in the NR2F1 gene. There are presently 28 cases of BBSOAS described in the literature. Its common features include developmental delay, intellectual disability, hypotonia, optic nerve atrophy, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, and thinning of the corpus callosum. Here we report two unrelated probands with novel, de novo, missense variants in NR2F1 The first is a 14-yr-old male patient with hypotonia, intellectual disability, optic nerve hypoplasia, delayed bone age, short stature, and altered neurotransmitter levels on cerebrospinal fluid testing. The second is a 5-yr-old female with severe developmental delay, motor and speech delay, and repetitive motion behavior. Whole-exome sequencing identified a novel missense NR2F1 variant in each case, Cys86Phe in the DNA-binding domain in Case 1, and a Leu372Pro in the ligand-binding domain in Case 2. The presence of clinical findings compatible with BBSOAS along with structural analysis at atomic resolution using homology-based molecular modeling and molecular dynamic simulations, support the pathogenicity of these variants for BBSOAS. Short stature, abnormal CNS neurotransmitters, and macrocephaly have not been previously reported for this syndrome and may represent a phenotypic expansion of BBSOAS. A review of published cases along with new evidence from this report support genotype-phenotype correlations for this disorder.


Assuntos
Fator I de Transcrição COUP/genética , Fator I de Transcrição COUP/metabolismo , Atrofias Ópticas Hereditárias/genética , Adolescente , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , DNA , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Exoma/genética , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Modelos Moleculares , Hipotonia Muscular/genética , Mutação/genética , Atrofias Ópticas Hereditárias/metabolismo , Atrofia Óptica/genética , Convulsões/genética , Sequenciamento Completo do Exoma
10.
Am J Hum Genet ; 101(4): 503-515, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28942966

RESUMO

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.


Assuntos
Anormalidades Múltiplas/genética , Antígenos Nucleares/genética , Anormalidades Craniofaciais/genética , Regulação da Expressão Gênica no Desenvolvimento , Haploinsuficiência/genética , Transtornos do Desenvolvimento da Linguagem/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Adolescente , Animais , Antígenos Nucleares/metabolismo , Sistemas CRISPR-Cas , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Anormalidades Craniofaciais/patologia , Feminino , Edição de Genes , Haploinsuficiência/fisiologia , Humanos , Transtornos do Desenvolvimento da Linguagem/patologia , Larva/genética , Larva/crescimento & desenvolvimento , Masculino , Microcefalia/patologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
11.
Am J Med Genet A ; 173(11): 3114-3117, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28940926

RESUMO

CHAND syndrome is an autosomal recessive disorder characterized by curly hair, ankyloblepharon, and nail dysplasia. Only few patients were reported to date. A homozygous RIPK4 mutation was recently identified by homozygosity mapping and whole exome sequencing in three patients from an expanded consanguineous kindred with a clinical diagnosis of CHAND syndrome. RIPK4 was previously known to be implicated in Bartsocas-Papas syndrome, the autosomal recessive form of popliteal pterygium syndrome. We report here two cases of RIPK4 homozygous mutations in a fetus with severe Bartsocas-Papas syndrome and a patient with CHAND syndrome. The patient with CHAND syndrome harbored the same mutation as the one identified in the family previously reported. We thus confirm the implication of RIPK4 gene in CHAND syndrome in addition to Bartsocas-Papas syndrome and discuss genotype/phenotype correlations.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Anormalidades do Olho/genética , Doenças Palpebrais/genética , Doenças do Cabelo/genética , Joelho/anormalidades , Transtornos do Desenvolvimento da Linguagem/genética , Unhas Malformadas/genética , Proteínas Serina-Treonina Quinases/genética , Sindactilia/genética , Pré-Escolar , Fenda Labial/diagnóstico , Fenda Labial/fisiopatologia , Fissura Palatina/diagnóstico , Fissura Palatina/fisiopatologia , Consanguinidade , Exoma/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Doenças Palpebrais/diagnóstico , Doenças Palpebrais/fisiopatologia , Feminino , Feto , Doenças do Cabelo/diagnóstico , Doenças do Cabelo/fisiopatologia , Homozigoto , Humanos , Recém-Nascido , Joelho/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Mutação , Unhas Malformadas/diagnóstico , Unhas Malformadas/fisiopatologia , Sindactilia/diagnóstico , Sindactilia/fisiopatologia
12.
Pediatrics ; 139(Suppl 3): S153-S171, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28814537

RESUMO

OBJECTIVES: The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families. METHODS: An electronic literature search was conducted, guided by a variety of key words. The search focused on 4 areas of both clinical and public health importance: (1) the full mutation phenotype, (2) developmental trajectories across the life span, (3) available interventions and treatments, and (4) impact on the family. A total of 661 articles were examined and 203 were included in the review. RESULTS: The information is presented in the following categories: developmental profile (cognition, language, functional skills, and transition to adulthood), social-emotional profile (cooccurring psychiatric conditions and behavior problems), medical profile (physical features, seizures, sleep, health problems, and physiologic features), treatment and interventions (educational/behavioral, allied health services, and pharmacologic), and impact on the family (family environment and financial impact). Research gaps also are presented. CONCLUSIONS: The identification and treatment of FXS remains an important public health and clinical concern. The information presented in this article provides a more robust understanding of FXS and the impact of this complex condition for pediatricians. Despite a wealth of information about the condition, much work remains to fully support affected individuals and their families.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Saúde Pública , Adulto , Cuidadores/psicologia , Criança , Estudos Transversais , Análise Mutacional de DNA , Assistência à Saúde , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Feminino , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/psicologia , Síndrome do Cromossomo X Frágil/terapia , Testes Genéticos , Humanos , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/psicologia , Transtornos do Desenvolvimento da Linguagem/terapia , Masculino , Poder Familiar/psicologia , Fenótipo , Prognóstico , Ajustamento Social , Repetições de Trinucleotídeos/genética
13.
Am J Med Genet A ; 173(10): 2659-2669, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28767196

RESUMO

Interstitial and terminal 6q25 deletions are associated with developmental delays, hypotonia, eye pathologies, craniofacial dysmorphologies, and structural brain anomalies. In most cases, speech and language deficits are not described in detail. We report on a case (Patient 1, age 7 years) with a de novo 6q25.3-qter deletion, 11.1 Mb long and encompassing 108 genes, and a case (Patient 2, age 5 years) with an inherited interstitial 6q25.3 deletion, located within Patient 1's deletion region and 403 kb long, the smallest 6q25 deletion reported to date. Both children have hypotonia, motor speech disorders, and expressive language delays. Patient 1's speech was characterized by childhood apraxia of speech (CAS) and dysarthria. Other findings include developmental delay, ataxic cerebral palsy, optic nerve dysplagia, and atypical brain morphologies regarding the corpus callosum and gyration patterns, a clinical profile that closely matches a previously reported case with a nearly identical deletion. Patient 2 had speech characterized by CAS and typical nonverbal processing abilities. His father, a carrier, had typical speech and language but showed difficulties with complex motor speech and hand motor tasks, similar to other adults with residual signs of CAS. The small deletion in this family contains the IGF2R-AIRN-SLC22A2-SLC22A3 gene cluster, which is associated with imprinting and maternal-specific expression of Igf2R, Slc22a2, and Slc22a3 in mice, whereas imprinting in humans is a polymorphic trait. The shared phenotypes in the two patients might be associated with the deletion of the gene cluster.


Assuntos
Cromossomos Humanos Par 6/genética , Deleção de Genes , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos dos Movimentos/genética , Distúrbios da Fala/genética , Adulto , Criança , Pré-Escolar , Feminino , Marcadores Genéticos , Humanos , Masculino , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico/genética , Receptor IGF Tipo 2/genética
14.
Neuropsychologia ; 103: 115-130, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28669897

RESUMO

Children begin to establish lexical-semantic representations during their first year of life, resulting in a rapid growth of vocabulary around 18-24 months of age. The neural mechanisms underlying this initial ability to map words onto conceptual representations remain relatively unknown. In the present study, the electrophysiological underpinnings of these mechanisms are explored during the critical phase of lexical acquisition using a picture-word matching paradigm. Event-Related Potentials (ERPs) elicited by words (either congruous or incongruous with the previous picture context) and pseudo-words are investigated in 20-month-old toddlers (N = 20) and compared to those elicited in a sample of adults (N = 20), reflecting the final and efficient system, and a sample of toddlers at familial risk for language and learning impairment (LLI, N = 15). The results suggest that the architecture underlying spoken word representation and processing is constant throughout development, even if some differences between children and adults emerged. Interestingly, children seem to be faster than adults in processing incongruent words, probably because relying on a different and more superficial strategy. This early strategy does not seem to be present in children at risk for LLI. In addition, both groups of children do not show different and specific electrophysiological underpinnings in response to real but incongruent words and unknown words, suggesting that during the critical phase of lexical acquisition any potential word is processed in a similar way. Overall, children at risk for LLI turned out to be sensitive to verbal incongruity of the lexical-semantic context, although some differences from typically developing children emerged, reflecting slower processing and less automatic responses. Taken together, the findings of this study pave the way to further research to investigate these effects in clinical and at-risk populations with the general purpose of disentangling the underlying mechanisms of lexical acquisition, and potentially predicting later language (dis)abilities.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Potenciais Evocados/fisiologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Transtornos de Aprendizagem/fisiopatologia , Semântica , Adulto , Análise de Variância , Encéfalo/fisiologia , Linguagem Infantil , Eletroencefalografia , Família , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos de Aprendizagem/genética , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Adulto Jovem
15.
Am J Med Genet A ; 173(9): 2494-2499, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28636205

RESUMO

We report on nine members of a consanguineous Pakistani family with primary presentation of intellectual disability, developmental delay, limb and gait ataxia, behavioral and speech problems, and tremor. By linkage mapping and exome sequencing we identified novel homozygous splicing variant c.6375-1G>C in SPTBN2. To date, only two other SPTBN2 mutations with recessive pattern of inheritance causing SCAR14 (spinocerebellar ataxia, autosomal recessive 14) that manifest with developmental ataxia and cognitive impairment, or cerebellar ataxia, mental retardation, and pyramidal signs have been reported. The mutation we identified is predicted to lead to the deletion of just the pleckstrin homology domain; thus, the earlier onset and more progressive nature of the disease in the presented family, as compared to earlier reports, were unexpected. No other mutation that could possibly explain the features that were unusual for SCAR14-arched palate, limb hypotonia, climacophobia, and behavioral problems-was identified. The disease was more severe in males than females. Our findings expand the recessive SPTBN2 mutation phenotype. We also review SPTBN2 mutation phenotypes. The gene encodes beta-III spectrin, which forms tetramers with alpha-II spectrin. The manifestations of this third recessive mutation suggest that for recessive mutations either no mutant protein is synthesized because the transcript is subject to nonsense-mediated decay or the mutant protein does not bind membrane proteins and, thus, does not exert a negative effect in heterozygotes, whereas the dominant mutations causing SCA5 form defective tetramers that compete with the native tetramers in binding membrane proteins, but are unable to anchor them.


Assuntos
Deficiências do Desenvolvimento/genética , Espectrina/genética , Ataxias Espinocerebelares/genética , Tremor/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Homozigoto , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Fenótipo , Comportamento Problema , Deleção de Sequência , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/fisiopatologia , Tremor/fisiopatologia , Adulto Jovem
16.
Cold Spring Harb Mol Case Stud ; 3(3): a001743, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28487885

RESUMO

Pathogenic variants in EBF3 were recently described in three back-to-back publications in association with a novel neurodevelopmental disorder characterized by intellectual disability, speech delay, ataxia, and facial dysmorphisms. In this report, we describe an additional patient carrying a de novo missense variant in EBF3 (c.487C>T, p.(Arg163Trp)) that falls within a conserved residue in the zinc knuckle motif of the DNA binding domain. Without a solved structure of the DNA binding domain, we generated a homology-based atomic model and performed molecular dynamics simulations for EBF3, which predicted decreased DNA affinity for p.(Arg163Trp) compared with wild-type protein and control variants. These data are in agreement with previous experimental studies of EBF1 showing the paralogous residue is essential for DNA binding. The conservation and experimental evidence existing for EBF1 and in silico modeling and dynamics simulations to validate comparable behavior of multiple variants in EBF3 demonstrates strong support for the pathogenicity of p.(Arg163Trp). We show that our patient presents with phenotypes consistent with previously reported patients harboring EBF3 variants and expands the phenotypic spectrum of this newly identified disorder with the additional feature of a bicornuate uterus.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Pré-Escolar , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Exoma , Feminino , Humanos , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação/genética , Mutação de Sentido Incorreto , Fenótipo , Fatores de Transcrição/metabolismo
17.
Clin Chim Acta ; 470: 42-45, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28438604

RESUMO

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare inherited disorder characterized by creatine (Cr) depletion and guanidinoacetate (GAA) accumulation in body fluids. We report the first identified Chinese case, diagnosed in a 4-year-old girl with onset of global developmental. Low Cr and high GAA levels were detected in her serum and urine, and low Cr level in her brain. Compound heterozygous variants in GAMT gene were found, including a previously reported variant at c.491dupG which was inherited from her mother and a novel variant at c.564G>T, which was inherited from her father. The Cr and GAA levels returned back to normal after 3 months of treatment. After one year of treatment, the patient stopped taking antiepileptic drugs and her electroencephalogram (EEG) was also back to normal. The girl was followed up for five years and exhibited good results beyond our expectation. The results have shown that protein restriction with high-dose ornithine and creatine supplements have strong therapeutic potential for our patient.


Assuntos
Guanidinoacetato N-Metiltransferase/deficiência , Transtornos do Desenvolvimento da Linguagem/tratamento farmacológico , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos dos Movimentos/congênito , Pré-Escolar , Creatina/farmacologia , Creatina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Guanidinoacetato N-Metiltransferase/genética , Guanidinoacetato N-Metiltransferase/metabolismo , Humanos , Transtornos do Desenvolvimento da Linguagem/enzimologia , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/enzimologia , Transtornos dos Movimentos/genética , Ornitina/farmacologia , Ornitina/uso terapêutico , Resultado do Tratamento
18.
Sci Rep ; 7: 46105, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28440294

RESUMO

A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential "multiple-hit" cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.


Assuntos
Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Transtornos do Desenvolvimento da Linguagem/genética , Mutação/genética , Segregação de Cromossomos/genética , Feminino , Ontologia Genética , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Fatores de Risco , Sequenciamento Completo do Exoma
19.
Am J Med Genet A ; 173(5): 1287-1293, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28371330

RESUMO

We present an 18-year-old boy with cerebral palsy, intellectual disability, speech delay, and seizures. He carries a likely pathogenic 1.3 Mb de novo heterozygous deletion in the 4q21.22 microdeletion syndrome region. He also carries a 436 kb maternally-inherited duplication impacting the first three exons of CHRNA7. The majority of previously published cases with 4q21.22 syndrome shared common features including growth restriction, muscular hypotonia, and absent or severely delayed speech. Using copy number variation (CNV) data available for other subjects, we defined a minimal critical region of 170.8 kb within the syndromic region, encompassing HNRNPD. We also identified a larger 2 Mb critical region encompassing ten protein-coding genes, of which six (PRKG2, RASGEF1B, HNRNPDL, HNRNPD, LIN54, COPS4) have a significantly low number of truncating loss-of-function mutations. Long-range chromatin interaction data suggest that this deletion may alter chromatin interactions at the 4q21.22 microdeletion region. We suggest that the deletion or misregulation of these genes is likely to contribute to the neurodevelopmental and neuromuscular abnormalities in 4q21.22 syndrome.


Assuntos
Paralisia Cerebral/genética , Cromossomos Humanos Par 4/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Adolescente , Paralisia Cerebral/fisiopatologia , Deleção Cromossômica , Variações do Número de Cópias de DNA/genética , Éxons/genética , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Receptor Nicotínico de Acetilcolina alfa7/genética
20.
Hum Genet ; 136(4): 377-386, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28251352

RESUMO

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Transporte/genética , Facies , Haploinsuficiência , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Transtorno do Espectro Autista/complicações , Criança , Pré-Escolar , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Transtornos do Desenvolvimento da Linguagem/complicações , Masculino
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