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1.
Exp Mol Pathol ; 115: 104471, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32446860

RESUMO

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Previously reported AKT3 variants are associated with various brain abnormalities and may lead to megalencephaly. MPPH syndrome is usually due to germline pathogenic AKT3 variants. Somatic mosaic pathogenic variants associated with hemimegalencephaly, which is similar to MPPH, have also been observed. A Hungarian Roma family with two half-siblings, which present with intellectual disability, dysmorphic features, epilepsy, brain malformations, and megalencephaly was studied. Whole exome sequencing (WES) analysis was performed. WES analysis revealed a heterozygous c.1393C > T p.(Arg465Trp) pathogenic missense AKT3 variant in both affected half-siblings. The variant was verified via Sanger sequencing and was not present in the DNA sample from the healthy mother, which was derived from peripheral blood, suggesting maternal germline mosaicism. In conclusion, this is the first report in which maternal germline mosaicism of a rare pathogenic AKT3 variant leads to autosomal dominantly inherited MPPH syndrome.


Assuntos
Dedos/anormalidades , Células Germinativas/metabolismo , Hidrocefalia/congênito , Padrões de Herança/genética , Megalencefalia/genética , Mosaicismo , Polidactilia/genética , Polimicrogiria/genética , Proteínas Proto-Oncogênicas c-akt/genética , Dedos do Pé/anormalidades , Adolescente , Criança , Feminino , Dedos/diagnóstico por imagem , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/genética , Imagem por Ressonância Magnética , Masculino , Megalencefalia/diagnóstico por imagem , Linhagem , Fenótipo , Polidactilia/diagnóstico por imagem , Polimicrogiria/diagnóstico por imagem , Irmãos , Síndrome , Dedos do Pé/diagnóstico por imagem
2.
Genes Dev ; 34(7-8): 580-597, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32115408

RESUMO

Dysregulation of early neurodevelopment is implicated in macrocephaly/autism disorders. However, the mechanism underlying this dysregulation, particularly in human cells, remains poorly understood. Mutations in the small GTPase gene RAB39b are associated with X-linked macrocephaly, autism spectrum disorder (ASD), and intellectual disability. The in vivo roles of RAB39b in the brain remain unknown. We generated Rab39b knockout (KO) mice and found that they exhibited cortical neurogenesis impairment, macrocephaly, and hallmark ASD behaviors, which resembled patient phenotypes. We also produced mutant human cerebral organoids that were substantially enlarged due to the overproliferation and impaired differentiation of neural progenitor cells (NPCs), which resemble neurodevelopmental deficits in KO mice. Mechanistic studies reveal that RAB39b interacts with PI3K components and its deletion promotes PI3K-AKT-mTOR signaling in NPCs of mouse cortex and cerebral organoids. The mTOR activity is robustly enhanced in mutant outer radial glia cells (oRGs), a subtype of NPCs barely detectable in rodents but abundant in human brains. Inhibition of AKT signaling rescued enlarged organoid sizes and NPC overproliferation caused by RAB39b mutations. Therefore, RAB39b mutation promotes PI3K-AKT-mTOR activity and alters cortical neurogenesis, leading to macrocephaly and autistic-like behaviors. Our studies provide new insights into neurodevelopmental dysregulation and common pathways associated with ASD across species.


Assuntos
Transtorno Autístico/genética , Córtex Cerebral/embriologia , Megalencefalia/genética , Neurogênese/genética , Proteínas rab de Ligação ao GTP/genética , Animais , Transtorno Autístico/fisiopatologia , Comportamento Animal/fisiologia , Diferenciação Celular/genética , Proliferação de Células/genética , Córtex Cerebral/citologia , Deleção de Genes , Humanos , Megalencefalia/fisiopatologia , Camundongos , Camundongos Knockout , Modelos Animais , Organoides/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética , Células-Tronco/citologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
3.
Neuron ; 106(3): 421-437.e11, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32126198

RESUMO

Autism is characterized by repetitive behaviors, impaired social interactions, and communication deficits. It is a prevalent neurodevelopmental disorder, and available treatments offer little benefit. Here, we show that genetically reducing the protein tau prevents behavioral signs of autism in two mouse models simulating distinct causes of this condition. Similar to a proportion of people with autism, both models have epilepsy, abnormally enlarged brains, and overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)/ mammalian target of rapamycin (mTOR) signaling pathway. All of these abnormalities were prevented or markedly diminished by partial or complete genetic removal of tau. We identify disinhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative PI3K regulator that tau controls, as a plausible mechanism and demonstrate that tau interacts with PTEN via tau's proline-rich domain. Our findings suggest an enabling role of tau in the pathogenesis of autism and identify tau reduction as a potential therapeutic strategy for some of the disorders that cause this condition.


Assuntos
Transtorno Autístico/genética , Megalencefalia/genética , Proteínas tau/genética , Animais , Transtorno Autístico/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Células HEK293 , Humanos , Megalencefalia/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , PTEN Fosfo-Hidrolase/química , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Domínios Proteicos Ricos em Prolina , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Proteínas tau/metabolismo
4.
Taiwan J Obstet Gynecol ; 59(1): 123-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039779

RESUMO

OBJECTIVE: We present the prenatal diagnosis of a class II 1q21.1 microdeletion in monozygotic (MZ) twins with discordant phenotypes. CASE REPORT: A monochorionic diamniotic twin pair presented with discordant ultrasound anomalies; twin A had cardiovascular abnormalities, while twin B did not. No specific complications were noted in the twins during pregnancy. A single nucleotide polymorphism array revealed an identical class II 1q21.1 microdeletion inherited from a phenotypically normal mother and identified the twins as MZ. The deleted region encompassed both the proximal 1q21.1 thrombocytopenia absent radius syndrome region and the distal 1q21.1 recurrent microdeletion region. No other rare copy number variants (CNVs) were identified, and concordance was observed in the CNVs between the twins. CONCLUSION: Discordant cardiovascular abnormalities may occur in MZ twins carrying the same class II 1q21.1 microdeletion. Further studies involving discordant MZ twins are needed to determine the modifying factors of the phenotypic heterogeneity of the microdeletion.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Cardiovasculares/diagnóstico , Doenças em Gêmeos/diagnóstico , Megalencefalia/diagnóstico , Diagnóstico Pré-Natal/métodos , Gêmeos Monozigóticos/genética , Anormalidades Múltiplas/genética , Adulto , Anormalidades Cardiovasculares/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Variações do Número de Cópias de DNA , Doenças em Gêmeos/genética , Feminino , Humanos , Megalencefalia/genética , Fenótipo , Gravidez , Gravidez de Gêmeos/genética
5.
Am J Med Genet C Semin Med Genet ; 181(4): 638-643, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714006

RESUMO

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.


Assuntos
Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Obesidade/genética , Fatores de Transcrição/genética , Adolescente , Criança , Humanos , Masculino , Índice de Gravidade de Doença , Síndrome
6.
Am J Med Genet C Semin Med Genet ; 181(4): 548-556, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31737996

RESUMO

The nucleosome remodeling and deacetylase (NuRD) complex is a major regulator of gene expression involved in pluripotency, lineage commitment, and corticogenesis. This important complex is composed of seven different proteins, with mutations in CHD3, CHD4, and GATAD2B being associated with neurodevelopmental disorders presenting with macrocephaly and intellectual disability similar to other overgrowth and intellectual disability (OGID) syndromes. Pathogenic variants in CHD3 and CHD4 primarily involve disruption of enzymatic function. GATAD2B variants include loss-of-function mutations that alter protein dosage and missense variants that involve either of two conserved domains (CR1 and CR2) known to interact with other NuRD proteins. In addition to macrocephaly and intellectual disability, CHD3 variants are associated with inguinal hernias and apraxia of speech; whereas CHD4 variants are associated with skeletal anomalies, deafness, and cardiac defects. GATAD2B-associated neurodevelopmental disorder (GAND) has phenotypic overlap with both of these disorders. Of note, structural models of NuRD indicate that CHD3 and CHD4 require direct contact with the GATAD2B-CR2 domain to interact with the rest of the complex. Therefore, the phenotypic overlaps of CHD3- and CHD4-related disorders with GAND are consistent with a loss in the ability of GATAD2B to recruit CHD3 or CHD4 to the complex. The shared features of these neurodevelopmental disorders may represent a new class of OGID syndrome: the NuRDopathies.


Assuntos
Megalencefalia/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/fisiologia , Transtornos do Neurodesenvolvimento/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Síndrome
7.
Taiwan J Obstet Gynecol ; 58(6): 859-863, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31759543

RESUMO

OBJECTIVE: We present detection of a familial 1q21.1 microdeletion and concomitant CHD1L mutation in a fetus with oligohydramnios and bilateral renal dysplasia on prenatal ultrasound. CASE REPORT: A 37-year-old, primigravid woman was referred for level II ultrasound examination at 16 weeks of gestation because of oligohydramnios. The parents were phenotypically normal, and there were no congenital malformations in the family. Prenatal ultrasound at 17 weeks of gestation revealed a fetus with fetal growth biometry equivalent to 16 weeks, oligohydramnios with an amniotic fluid index (AFI) of 1.4 cm and bilateral renal dysplasia without sonographic demonstration of bilateral renal arteries. The pregnancy was subsequently terminated, and a 137-g fetus was delivered without characteristic facial dysmorphism. Postnatal cytogenetic analysis of the umbilical cord and parental bloods revealed normal karyotypes. However, array comparative genomic hybridization (aCGH) analysis on the DNA extracted from the umbilical cord revealed a 2.038-Mb microdeletion of 1q21.1-q21.2 encompassing 11 [Online Mendelian Inheritance in Man (OMIM)] genes of PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, GPR89B, NBPF14, TRN-GTT2-1 and NBPF20. The mother was found to carry the same microdeletion. A missense mutation of c.2353T > G, p.Ser785Ala in CHD1L was detected in the umbilical cord. The father was found to carry a heterozygous mutation of c.2353T > G, p.Ser785Ala in CHD1L. CONCLUSION: Fetuses with a 1q21.1 microdeletion and concomitant CHD1L mutation may present oligohydramnios and bilateral renal dysplasia on prenatal ultrasound.


Assuntos
Anormalidades Múltiplas/diagnóstico , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Túbulos Renais Proximais/anormalidades , Megalencefalia/diagnóstico , Mutação de Sentido Incorreto , Oligo-Hidrâmnio/diagnóstico , Ultrassonografia Pré-Natal/métodos , Anormalidades Urogenitais/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 1/metabolismo , DNA/genética , DNA Helicases/metabolismo , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Megalencefalia/genética , Megalencefalia/metabolismo , Oligo-Hidrâmnio/genética , Gravidez , Anormalidades Urogenitais/genética
8.
Am J Med Genet C Semin Med Genet ; 181(4): 582-590, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31441589

RESUMO

Megalencephaly (MEG) is a developmental abnormality of brain growth characterized by early onset, often progressive, brain overgrowth. Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K-AKT-MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype-phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and/or autism spectrum disorder; moderately activating variants (that are typically high-level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low-level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K-AKT-MTOR pathway inhibitors.


Assuntos
Megalencefalia/genética , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Humanos , Megalencefalia/metabolismo , Síndrome
10.
Epilepsia ; 60(6): e67-e73, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31111464

RESUMO

Despite tremendous progress through next generation sequencing technologies, familial focal epilepsies are insufficiently understood. We sought to identify the genetic basis in multiplex Palestinian families with familial focal epilepsy with variable foci (FFEVF). Family I with 10 affected individuals and Family II with five affected individuals underwent detailed phenotyping over three generations. The phenotypic spectrum of the two families varied from nonlesional focal epilepsy including nocturnal frontal lobe epilepsy to severe structural epilepsy due to hemimegalencephaly. Whole-exome sequencing and single nucleotide polymorphism array analysis revealed pathogenic variants in NPRL3 in each family, a partial ~38-kb deletion encompassing eight exons (exons 8-15) and the 3'-untranslated region of the NPRL3 gene in Family I, and a de novo nonsense variant c.1063C>T, p.Gln355* in Family II. Furthermore, we identified a truncating variant in the PDCD10 gene in addition to the NPRL3 variant in a patient with focal epilepsy from Family I. The individual also had developmental delay and multiple cerebral cavernomas, possibly demonstrating a digenic contribution to the individual's phenotype. Our results implicate the association of NPRL3 with hemimegalencephaly, expanding the phenotypic spectrum of NPRL3 in FFEVF and underlining that partial deletions are part of the genotypic spectrum of NPRL3 variants.


Assuntos
Epilepsias Parciais/complicações , Epilepsias Parciais/genética , Proteínas Ativadoras de GTPase/genética , Megalencefalia/etiologia , Megalencefalia/genética , Adolescente , Adulto , Idade de Início , Proteínas Reguladoras de Apoptose/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Epilepsia do Lobo Frontal/complicações , Epilepsia do Lobo Frontal/genética , Exoma/genética , Família , Feminino , Deleção de Genes , Variação Genética , Genótipo , Humanos , Lactente , Masculino , Proteínas de Membrana/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas/genética
11.
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
12.
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
13.
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
14.
EBioMedicine ; 39: 388-400, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30503862

RESUMO

BACKGROUND: Nuclear Factor One X (NFIX) haploinsufficiency in humans results in Malan syndrome, a disorder characterized by overgrowth, macrocephaly and intellectual disability. Although clinical assessments have determined the underlying symptomology of Malan syndrome, the fundamental mechanisms contributing to the enlarged head circumference and intellectual disability in these patients remains undefined. METHODS: Here, we used Nfix heterozygous mice as a model to investigate these aspects of Malan syndrome. Volumetric magnetic resonance imaging (MRI) was used to calculate the volumes of 20 brain sub regions. Diffusion tensor MRI was used to perform tractography-based analyses of the corpus callosum, hippocampal commissure, and anterior commissure, as well as structural connectome mapping of the whole brain. Immunohistochemistry examined the neocortical cellular populations. Two behavioral assays were performed, including the active place avoidance task to assess spatial navigation and learning and memory function, and the 3-chambered sociability task to examine social behaviour. FINDINGS: Adult Nfix+/- mice exhibit significantly increased brain volume (megalencephaly) compared to wildtypes, with the cerebral cortex showing the highest increase. Moreover, all three forebrain commissures, in particular the anterior commissure, revealed significantly reduced fractional anisotropy, axial and radial diffusivity, and tract density intensity. Structural connectome analyses revealed aberrant connectivity between many crucial brain regions. Finally, Nfix+/- mice exhibit behavioral deficits that model intellectual disability. INTERPRETATION: Collectively, these data provide a significant conceptual advance in our understanding of Malan syndrome by suggesting that megalencephaly underlies the enlarged head size of these patients, and that disrupted cortical connectivity may contribute to the intellectual disability these patients exhibit. FUND: Australian Research Council (ARC) Discovery Project Grants, ARC Fellowship, NYSTEM and Australian Postgraduate Fellowships.


Assuntos
Córtex Cerebral/diagnóstico por imagem , Haploinsuficiência , Deficiência Intelectual/genética , Megalencefalia/genética , Fatores de Transcrição NFI/genética , Animais , Conectoma , Modelos Animais de Doenças , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/psicologia , Imagem por Ressonância Magnética , Masculino , Megalencefalia/diagnóstico por imagem , Megalencefalia/psicologia , Camundongos , Tamanho do Órgão , Aprendizagem Espacial
15.
Am J Med Genet A ; 179(3): 475-479, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30569621

RESUMO

Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling result in brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri-color of the Blaschko-linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C > T (p.Thr1977Ile) MTOR variant. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings. We report a fourth case of a 3-year-old female presenting with megalencephaly, obstructive hydrocephalus due to cerebral aqueductal stenosis, asymmetric polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism. Oligonucleotide and SNP chromosomal microarray (CMA), karyotype, and trio whole exome sequencing (WES) in the peripheral blood, as well as a targeted gene variant panel from fibroblasts derived from hyperpigmented and non-hyperpigmented skin did not detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes. Unlike the previously reported cases, the de novo c.5930C > T (p.Thr1977Ile) MTOR variant was detected at 32% mosaicism in our patient only after WES was performed on fibroblast-derived DNA from the hyperpigmented skin. This case demonstrates the tissue variability in mosaic expression of the recurrent p.Thr1977Ile MTOR variant, emphasizes the need for skin biopsies in the genetic evaluation of patients with skin pigmentary mosaicism, and expands the clinical phenotype associated with this pathogenic MTOR variant.


Assuntos
Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/genética , Megalencefalia/diagnóstico , Megalencefalia/genética , Mutação , Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genética , Serina-Treonina Quinases TOR/genética , Alelos , Substituição de Aminoácidos , Pré-Escolar , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Mosaicismo , Fenótipo , Polimorfismo de Nucleotídeo Único
16.
Eur J Med Genet ; 62(12): 103587, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30472487

RESUMO

Expression of the fusion genes is considered to be an important mechanism of tumorigenesis. However it is hardly ever discussed in relation to the neurodevelopmental disorders. Here we report on an 18-years-old female patient with 13.1 kb deletion of 8q24.3 fusing the 5'-portion of SCRIB with the 3'-portion of PUF60 and presenting with borderline intellectual disability, eye coloboma, short stature, scoliosis, heart defects and interestingly postnatal megalencephaly, in contrast to microcephaly, which is usually associated with 8q24.3 deletion (Verheij syndrome). Using next generation sequencing we mapped the breakpoints at nucleotide resolution and showed that the deletion preserved the reading frame. In contrast to the laborious techniques previously used for the precise mapping of deletion breakpoints, our approach identified an accurate interval very rapidly. We demonstrated the expression of the PUF60-SCRIB fusion gene in patient's cells and suggest that the fusion transcript might be a cause of the atypical clinical presentation.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Coloboma/genética , Fusão Gênica , Deficiência Intelectual/genética , Megalencefalia/genética , Escoliose/genética , Adolescente , Pontos de Quebra do Cromossomo , Coloboma/patologia , Feminino , Humanos , Deficiência Intelectual/patologia , Megalencefalia/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Escoliose/patologia , Síndrome , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
18.
Eur J Med Genet ; 62(12): 103596, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30528446

RESUMO

OBJECTIVE OF THE STUDY: To give a full overview of the clinical presentation of PTEN mutations in pediatric patients and to propose a pediatric follow-up protocol. METHODS: Recruitment of 16 PTEN mutated children (age 6 months-11 years) from two pediatric centers in Milan (Italy) between 2006 and 2017. All the patients underwent clinical and neurologic evaluations, cognitive and behavioral tests, and brain MRI; they are currently following an oncologic follow-up. RESULTS: Extreme macrocephaly is present in all the patients (69% HC above +4 SD). Neuropsychiatric issues have high prevalence, with 56% of patients showing developmental delay and 25% showing autism spectrum disorder. Brain MRI reveals in 75% of the patients at least one of the following: enlarged perivascular spaces, white matter anomalies, and/or downward displacement of the cerebellar tonsils through the foramen magnum, resulting in Chiari I malformation in two patients. Vascular malformations have a prevalence of 19%, with further evidence that complex cardiovascular malformations may be related to PTEN mutations; 31% of patients present hamartomas. None of our patients have so far experienced any oncologic complication. CONCLUSIONS: We suggest to screen for PTEN mutations all children presenting macrocephaly and one of the following: neurodevelopmental issues, one of the three major brain MRI anomalies, cutaneous lesions, vascular malformations, family history positive for PTEN related malignancies; or also with macrocephaly alone when exceeding +3 SD. Basing on our cohort results and further recent studies on the condition, we recommend a follow-up protocol that includes annual clinical and dermatological examination, thyroid and abdominal US, and Fecal Occult Blood test plus neurodevelopmental evaluation, heart US (to exclude congenital heart malformations), and brain MRI (to exclude Chiari I malformation) at diagnosis.


Assuntos
Transtorno do Espectro Autista/genética , Anormalidades Cardiovasculares/genética , Megalencefalia/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Fenótipo , Transtorno do Espectro Autista/patologia , Anormalidades Cardiovasculares/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Megalencefalia/patologia , Síndrome
19.
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
20.
Am J Hum Genet ; 103(5): 752-768, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.


Assuntos
Haploinsuficiência/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Fatores de Transcrição NFI/genética , Adolescente , Adulto , Animais , Córtex Cerebral/patologia , Criança , Pré-Escolar , Códon sem Sentido/genética , Estudos de Coortes , Corpo Caloso/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
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