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1.
Seizure ; 66: 81-85, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30818181

RESUMO

PURPOSE: Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly. METHODS: We use family-based whole-exome sequencing to identify candidate variants. RESULTS: We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein. CONCLUSION: Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.


Assuntos
Epilepsia/genética , Saúde da Família , Deficiência Intelectual/genética , Megalencefalia/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adulto , Análise Mutacional de DNA , Epilepsia/complicações , Epilepsia/diagnóstico por imagem , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Megalencefalia/complicações , Megalencefalia/diagnóstico por imagem , Sequenciamento Completo do Exoma , Adulto Jovem
2.
Nat Rev Endocrinol ; 15(5): 299-311, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30842651

RESUMO

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.


Assuntos
Neoplasias/epidemiologia , Neoplasias/genética , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/epidemiologia , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Megalencefalia/epidemiologia , Megalencefalia/genética , Megalencefalia/patologia , Neoplasias/patologia , Gravidez , Fatores de Risco , Síndrome de Sotos/epidemiologia , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Síndrome
3.
J Hum Genet ; 64(4): 271-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30670789

RESUMO

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Facies , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia
4.
PLoS Genet ; 14(12): e1007623, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566533

RESUMO

The human 1q21.1 deletion of ten genes is associated with increased risk of schizophrenia. This deletion involves the ß-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for energy and low capacity to store nutrients, the role of AMPK in neuronal physiology is poorly defined. Here we show that AMPK is important in the nervous system for maintaining neuronal integrity and for stress survival and longevity in Drosophila. To understand the impact of this signaling system on behavior and its potential contribution to the 1q21.1 deletion syndrome, we focused on sleep, an important role of which is proposed to be the reestablishment of neuronal energy levels that are diminished during energy-demanding wakefulness. Sleep disturbances are one of the most common problems affecting individuals with psychiatric disorders. We show that AMPK is required for maintenance of proper sleep architecture and for sleep recovery following sleep deprivation. Neuronal AMPKß loss specifically leads to sleep fragmentation and causes dysregulation of genes believed to play a role in sleep homeostasis. Our data also suggest that AMPKß loss may contribute to the increased risk of developing mental disorders and sleep disturbances associated with the human 1q21.1 deletion.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Anormalidades Múltiplas/enzimologia , Anormalidades Múltiplas/genética , Megalencefalia/enzimologia , Megalencefalia/genética , Neurônios/enzimologia , Esquizofrenia/enzimologia , Esquizofrenia/genética , Sono/genética , Sono/fisiologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/deficiência , Animais , Deleção Cromossômica , Cromossomos Humanos Par 1/enzimologia , Cromossomos Humanos Par 1/genética , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Humanos , Aprendizagem/fisiologia , Longevidade/genética , Longevidade/fisiologia , Masculino , Modelos Animais , Neurônios/citologia , Fatores de Risco , Transdução de Sinais , Transtornos do Sono-Vigília/enzimologia , Transtornos do Sono-Vigília/genética
5.
Brain Dev ; 40(8): 678-684, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29752200

RESUMO

BACKGROUND: Germline mutations of the PTEN gene are responsible for several PTEN hamartoma tumor syndromes. They are also implicated as a cause of macrocephaly and mild to severe developmental delay, regardless of the presence or absence of hamartomas in childhood. Nevertheless, because of limited information, the clinical features present during childhood in patients with a PTEN mutation are yet to be elucidated. METHODS: PTEN mutations were investigated by multiplex targeted sequencing of genomic DNA from 33 children with increased head circumference (>+2 SD) and developmental delay. The clinical features of all the patients with a PTEN mutation were abstracted by dysmorphologists. RESULTS: We have identified six children with a PTEN mutation. Clinical dissection of these six patients, in addition to patient reports in the literature, revealed distinctive facial features that included frontal bossing, dolichocephaly, horizontal eyebrows, and a depressed nasal bridge. Macrocephaly (+3.2 to +6.0 SD) was noticeable compared to their height (-0.8 to +2.1 SD), and the difference in the SD value of head circumference and height was more than 3 SD in all patients. CONCLUSION: The presence of distinctive facies, extreme macrocephaly with normal to mildly high stature, and developmental delay may be useful for identifying patients with a PTEN mutation in childhood. Early identification of patients with a PTEN mutation would help uncover the natural course of tumor development in this group of individuals who have a possible predisposition to cancer, and be important for the development of an optimal surveillance strategy.


Assuntos
Deficiências do Desenvolvimento/genética , Face/anormalidades , Megalencefalia/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Feminino , Humanos , Masculino , Megalencefalia/diagnóstico por imagem , Fenótipo
6.
Pediatr Dermatol ; 35(3): e186-e188, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29493003

RESUMO

A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.


Assuntos
Anormalidades Múltiplas/diagnóstico , Classe I de Fosfatidilinositol 3-Quinases/genética , Lipoma/diagnóstico , Megalencefalia/diagnóstico , Anormalidades Musculoesqueléticas/diagnóstico , Nevo/diagnóstico , Dermatopatias Vasculares/diagnóstico , Telangiectasia/congênito , Malformações Vasculares/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Sequência de Bases , Broncodilatadores/uso terapêutico , Diagnóstico Diferencial , Nutrição Enteral , Humanos , Imunossupressores/uso terapêutico , Recém-Nascido , Lipoma/genética , Lipoma/terapia , Masculino , Megalencefalia/genética , Megalencefalia/terapia , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/terapia , Mutação , Nevo/genética , Nevo/terapia , Fenótipo , Respiração Artificial/métodos , Sirolimo/uso terapêutico , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/terapia , Telangiectasia/diagnóstico , Telangiectasia/genética , Telangiectasia/terapia , Malformações Vasculares/genética , Malformações Vasculares/terapia
7.
Mol Genet Genomic Med ; 6(1): 92-98, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29222831

RESUMO

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects. METHODS: We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS. RESULTS: We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS. CONCLUSION: Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.


Assuntos
Encéfalo/fisiopatologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Anormalidades Múltiplas/genética , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Pré-Escolar , Cromossomos Humanos Par 12/genética , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Cariotipagem , Masculino , Malformações do Desenvolvimento Cortical/genética , Megalencefalia/genética , Mosaicismo , Tetrassomia/genética
8.
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
9.
Genet Med ; 20(1): 142-150, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28726812

RESUMO

PurposeHeterozygous germ-line activating mutations in PDGFRB cause Kosaki and Penttinen syndromes and myofibromatosis. We describe a 10-year-old child with a germ-line PDGFRB p.N666H mutation who responded to the tyrosine kinase inhibitor imatinib by inhibition of PDGFRB.MethodsThe impact of p.N666H on PDGFRB function and sensitivity to imatinib was studied in cell culture.ResultsCells expressing the p.N666H mutation showed constitutive PDGFRB tyrosine phosphorylation. PDGF-independent proliferation was abolished by imatinib at 1 µM concentration. Patient fibroblasts showed constitutive receptor tyrosine phosphorylation that was also abrogated by imatinib with reduced proliferation of treated cells.This led to patient treatment with imatinib at 400 mg daily (340 mg/m2) for a year with objective improvement of debilitating hand and foot contractures, reduced facial coarseness, and significant improvement in quality of life. New small subcutaneous nodules developed, but remained stable. Transient leukopenia, neutropenia, and fatigue resolved without intervention; however, mildly decreased growth velocity resulted in reducing imatinib dose to 200 mg daily (170 mg/m2). The patient continues treatment with ongoing clinical response.ConclusionTo our knowledge, this is one of the first personalized treatments of a congenital disorder caused by a germ-line PDGF receptor mutation with a PDGFRB inhibitor.


Assuntos
Alelos , Substituição de Aminoácidos , Mutação com Ganho de Função , Mutação em Linhagem Germinativa , Mesilato de Imatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Testes Genéticos , Humanos , Mesilato de Imatinib/farmacologia , Lactente , Imagem por Ressonância Magnética , Masculino , Megalencefalia/diagnóstico , Megalencefalia/genética , Megalencefalia/cirurgia , Miofibromatose/congênito , Miofibromatose/diagnóstico , Miofibromatose/tratamento farmacológico , Miofibromatose/genética , Farmacogenética , Inibidores de Proteínas Quinases/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Resultado do Tratamento
10.
Brain Dev ; 40(2): 134-139, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28893434

RESUMO

Mutations in SZT2 were first reported in 2013 as a cause of early-onset epileptic encephalopathy. Because only five reports have been published to date, the clinical features associated with SZT2 remain unclear. We herein report an additional patient with biallelic mutations in SZT2. The proband, a four-year-old girl, showed developmental delay and seizures from two years of age. Her seizures were not intractable and readily controlled by valproate. She showed mildly dysmorphic facies with macrocephaly, high forehead, and hypertelorism, and also had pectus carinatum. An EEG showed epileptic discharges which rarely occurred. A brain MRI revealed a short and thick corpus callosum. Whole-exome sequencing detected compound heterozygous biallelic mutations (c.8596dup (p.Tyr2866Leufs∗42) and c.2930-17_2930-3delinsCTCGTG) in SZT2, both of which were novel and predicted to be truncating. This case suggested a broad phenotypic spectrum arises from SZT2 mutations, forming a continuum from epileptic encephalopathy and severe developmental delay to mild intellectual disability without epilepsy. The characteristic thick and short corpus callosum observed in 7/8 cases with epilepsy, including the proband, but not in three non-syndromic cases, appears to be specific, and thus useful for indicating the possibility of SZT2 mutations. This feature has the potential to make loss of SZT2 a clinically discernible disorder despite a wide clinical spectrum.


Assuntos
Agenesia do Corpo Caloso/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Megalencefalia/genética , Mutação , Proteínas do Tecido Nervoso/genética , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/fisiopatologia , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Humanos , Megalencefalia/diagnóstico por imagem , Megalencefalia/fisiopatologia , Fenótipo
11.
Dialogues Clin Neurosci ; 20(4): 267-282, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30936767

RESUMO

Expansion of the human brain, and specifically the neocortex, is among the most remarkable evolutionary processes that correlates with cognitive, emotional, and social abilities. Cortical expansion is determined through a tightly orchestrated process of neural stem cell proliferation, migration, and ongoing organization, synaptogenesis, and apoptosis. Perturbations of each of these intricate steps can lead to abnormalities of brain size in humans, whether small (microcephaly) or large (megalencephaly). Abnormalities of brain growth can be clinically isolated or occur as part of complex syndromes associated with other neurodevelopmental problems (eg, epilepsy, autism, intellectual disability), brain malformations, and body growth abnormalities. Thorough review of the genetic literature reveals that human microcephaly and megalencephaly are caused by mutations of a rapidly growing number of genes linked within critical cellular pathways that impact early brain development, with important pathomechanistic links to cancer, body growth, and epilepsy. Given the rapid rate of causal gene identification for microcephaly and megalencephaly understanding the roles and interplay of these important signaling pathways is crucial to further unravel the mechanisms underlying brain growth disorders and, more fundamentally, normal brain growth and development in humans. In this review, we will (a) overview the definitions of microcephaly and megalencephaly, highlighting their classifications in clinical practice; (b) overview the most common genes and pathways underlying microcephaly and megalencephaly based on the fundamental cellular processes that are perturbed during cortical development; and (c) outline general clinical molecular diagnostic workflows for children and adults presenting with microcephaly and megalencephaly.


Assuntos
Encéfalo/patologia , Megalencefalia/patologia , Microcefalia/patologia , Tamanho do Órgão/fisiologia , Transtorno Autístico/genética , Transtorno Autístico/patologia , Humanos , Megalencefalia/genética , Microcefalia/diagnóstico , Microcefalia/genética , Mutação/genética
12.
Cell Rep ; 21(10): 2678-2687, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29212016

RESUMO

A deletion or duplication in the 16p11.2 region is associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. In addition to clinical characteristics, carriers of the 16p11.2 copy-number variant (CNV) manifest opposing neuroanatomical phenotypes-e.g., macrocephaly in deletion carriers (16pdel) and microcephaly in duplication carriers (16pdup). Using fibroblasts obtained from 16pdel and 16pdup carriers, we generated induced pluripotent stem cells (iPSCs) and differentiated them into neurons to identify causal cellular mechanisms underlying neurobiological phenotypes. Our study revealed increased soma size and dendrite length in 16pdel neurons and reduced neuronal size and dendrite length in 16pdup neurons. The functional properties of iPSC-derived neurons corroborated aspects of these contrasting morphological differences that may underlie brain size. Interestingly, both 16pdel and 16pdup neurons displayed reduced synaptic density, suggesting that distinct mechanisms may underlie brain size and neuronal connectivity at this locus.


Assuntos
Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Deleção Cromossômica , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA/genética , Humanos , Megalencefalia/genética , Megalencefalia/metabolismo , Microcefalia/genética , Microcefalia/metabolismo , Modelos Genéticos
14.
Mol Autism ; 8: 59, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29152164

RESUMO

Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results: Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions: Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated.


Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Proteínas rab de Ligação ao GTP/genética , Alelos , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Sistemas CRISPR-Cas/genética , Células Cultivadas , Criança , Códon sem Sentido , Feminino , Fibroblastos/citologia , Genótipo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Masculino , Megalencefalia/complicações , Megalencefalia/diagnóstico , Linhagem , Fenótipo , Sequenciamento Completo do Genoma , Proteínas rab de Ligação ao GTP/deficiência
15.
Nat Commun ; 8(1): 1052, 2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-29051493

RESUMO

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.


Assuntos
Encéfalo/anatomia & histologia , Deficiência Intelectual/genética , Megalencefalia/genética , Mutação , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Serina-Treonina Quinases TOR/metabolismo , Animais , Movimento Celular , Tamanho Celular , Células Cultivadas , Humanos , Deficiência Intelectual/patologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Tamanho do Órgão , Convulsões/genética , Transdução de Sinais/genética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Peixe-Zebra/genética
16.
Brain ; 140(10): 2610-2622, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28969385

RESUMO

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.


Assuntos
Deficiências do Desenvolvimento/genética , Megalencefalia/genética , Mutação/genética , Proteínas Proto-Oncogênicas c-akt/genética , Encéfalo/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Feminino , Estudos de Associação Genética , Células HEK293 , Humanos , Imunoprecipitação , Imagem por Ressonância Magnética , Masculino , Megalencefalia/diagnóstico por imagem , Megalencefalia/patologia , Mutagênese Sítio-Dirigida/métodos , Fosfatidilinositóis/metabolismo , Transfecção
17.
Eur J Med Genet ; 60(12): 650-654, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28899818

RESUMO

Because several genes responsible for epileptic encephalopathy are located on the 9q33q34 region, patients with chromosomal deletions of this region often show intractable epilepsy and neurodevelopmental disability. Contrary to these findings, chromosomal duplications of this region have never been reported previously. We identified a first case of 9q33q34 microduplications in siblings associated with developmental disorders and macrocephaly. Their mother was a mosaic carrier of this duplication. Duplicated regions involved STXBP1; the gene related to epileptic encephalopathy. Neurological features including developmental delay and macrocephaly observed in the present siblings may be derived from the extra-copy of STXBP1.


Assuntos
Transtornos Cromossômicos/genética , Duplicação Cromossômica , Cromossomos Humanos Par 9/genética , Deficiências do Desenvolvimento/genética , Megalencefalia/genética , Adulto , Criança , Pré-Escolar , Transtornos Cromossômicos/diagnóstico , Deficiências do Desenvolvimento/diagnóstico , Feminino , Heterozigoto , Humanos , Masculino , Megalencefalia/diagnóstico , Mosaicismo , Proteínas Munc18/genética , Irmãos
18.
Am J Med Genet A ; 173(12): 3158-3164, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28941020

RESUMO

The association between 1p32-p31 contiguous gene deletions and a distinct phenotype that includes anomalies of the corpus callosum, ventriculomegaly, developmental delay, seizures, and dysmorphic features has been long recognized and described. Recently, the observation of overlapping phenotypes in patients with chromosome translocations that disrupt NFIA (Nuclear factor I/A), a gene within this deleted region, and NFIA intragenic deletions has led to the hypothesis that NFIA is a critical gene within this region. The wide application and increasing accessibility of whole exome sequencing (WES) has helped identify new cases to support this hypothesis. Here, we describe four patients with loss-of-function variants in the NFIA gene identified through WES. The clinical presentation of these patients significantly overlaps with the phenotype described in previously reported cases of 1p32-p31 deletion syndrome, NFIA gene disruptions and intragenic NFIA deletions. Our cohort includes a mother and daughter as well as an unrelated individual who share the same nonsense variant (c.205C>T, p.Arg69Ter; NM_001145512.1). We also report a patient with a frameshift NFIA variant (c.159_160dupCC, p.Gln54ProfsTer49). We have compared published cases of 1p32-p31 microdeletion syndrome, translocations resulting in NFIA gene disruption, intragenic deletions, and loss-of-function mutations (including our four patients) to reveal that abnormalities of the corpus callosum, ventriculomegaly/hydrocephalus, macrocephaly, Chiari I malformation, dysmorphic features, developmental delay, hypotonia, and urinary tract defects are common findings. The consistent overlap in clinical presentation provides further evidence of the critical role of NFIA haploinsufficiency in the development of the 1p32-p31 microdeletion syndrome phenotype.


Assuntos
Agenesia do Corpo Caloso/genética , Malformação de Arnold-Chiari/genética , Deficiências do Desenvolvimento/genética , Megalencefalia/genética , Fatores de Transcrição NFI/genética , Malformações do Sistema Nervoso/genética , Adolescente , Adulto , Agenesia do Corpo Caloso/diagnóstico , Malformação de Arnold-Chiari/diagnóstico , Criança , Deleção Cromossômica , Cromossomos Humanos Par 1 , Estudos de Coortes , Deficiências do Desenvolvimento/diagnóstico , Feminino , Haploinsuficiência , Humanos , Mutação com Perda de Função , Masculino , Megalencefalia/diagnóstico , Malformações do Sistema Nervoso/diagnóstico , Sequenciamento Completo do Exoma
19.
Mol Psychiatry ; 22(9): 1282-1290, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28831199

RESUMO

Autism spectrum disorder (ASD) represents a set of complex neurodevelopmental disorders with large degrees of heritability and heterogeneity. We sequenced 136 microcephaly or macrocephaly (Mic-Mac)-related genes and 158 possible ASD-risk genes in 536 Chinese ASD probands and detected 22 damaging de novo mutations (DNMs) in 20 genes, including CHD8 and SCN2A, with recurrent events. Nine of the 20 genes were previously reported to harbor DNMs in ASD patients from other populations, while 11 of them were first identified in present study. We combined genetic variations of the 294 sequenced genes from publicly available whole-exome or whole-genome sequencing studies (4167 probands plus 1786 controls) with our Chinese population (536 cases plus 1457 controls) to optimize the power of candidate-gene prioritization. As a result, we prioritized 67 ASD-candidate genes that exhibited significantly higher probabilities of haploinsufficiency and genic intolerance, and significantly interacted and co-expressed with each another, as well as other known ASD-risk genes. Probands with DNMs or rare inherited mutations in the 67 candidate genes exhibited significantly lower intelligence quotients, supporting their strong functional impact. In addition, we prioritized 39 ASD-related Mic-Mac-risk genes, and showed their interaction and co-expression in a functional network that converged on chromatin remodeling, synapse transmission and cell cycle progression. Genes within the three functional subnetworks exhibited distinct and recognizable spatiotemporal-expression patterns in human brains and laminar-expression profiles in the developing neocortex, highlighting their important roles in brain development. Our results indicate some of Mic-Mac-risk genes are involved in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Megalencefalia/genética , Microcefalia/genética , Transtorno do Espectro Autista/metabolismo , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Estudos de Casos e Controles , China , Proteínas de Ligação a DNA/genética , Exoma , Feminino , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Mutação , Fatores de Risco , Fatores de Transcrição/genética
20.
J Clin Endocrinol Metab ; 102(8): 3029-3039, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28605459

RESUMO

Context: Only a few genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, Prader-Willi syndrome) and nonsyndromic (16p11.2 deletions) obesity. Objective: To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue. Design and Setting: A case-control study in a tertiary academic center. Participants: CNV analysis was performed on 90 subjects with early-onset obesity and 67 normal-weight controls. Subcutaneous adipose tissue from body mass index-discordant siblings was used for the gene expression analyses. Main Outcome Measures: We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes, including all known obesity loci. The expression of candidate genes was assessed using microarray analysis of messenger RNA from subcutaneous adipose tissue. Results: We identified rare CNVs in 17 subjects (19%) with obesity and 2 controls (3%). In three cases (3%), the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion, and 16p11.2 deletion, respectively), although the others were not known. Seven CNVs in 10 families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for 10 genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR, and MBD5). Conclusions: Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.


Assuntos
Obesidade Pediátrica/genética , RNA Mensageiro/metabolismo , Gordura Subcutânea/metabolismo , Anormalidades Múltiplas/genética , Fosfatase Ácida/genética , Adolescente , Adulto , Proteínas Mutadas de Ataxia Telangiectasia/genética , Transtorno Autístico/genética , Autoantígenos/genética , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 22/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Síndrome de DiGeorge/genética , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Hidrolases/genética , Deficiência Intelectual/genética , Fatores de Transcrição Kruppel-Like/genética , Masculino , Megalencefalia/genética , Proteínas dos Microfilamentos/genética , Proteínas Nucleares/genética , Proteínas/genética , Irmãos , Fatores de Transcrição/genética , Transcriptoma , Adulto Jovem
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