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1.
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
2.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
3.
J Pediatr Endocrinol Metab ; 32(4): 409-413, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30796847

RESUMO

Background Obesity has become one of the greatest health risks worldwide. Recently, there was an explosion of information regarding the role of the central nervous system (CNS) in the development of monogenic and syndromic obesity. Case presentation Over the last decade, terminal and interstitial submicroscopic deletions of copy number variants (CNVs) in 2p25.3 and single nucleotide variants (SNVs) in myelin transcription factor 1 like (MYT1L) were detected by genome-wide array analysis and whole exome sequencing (WES) in patients with a nonspecific clinical phenotype that commonly includes intellectual disability (ID), early onset of obesity and speech delay. Here, we report the first Saudi female patient with mild to moderate ID, early onset of obesity and speech delay associated with a de novo pathogenic SNV in the MYT1L gene (c. 1585G>A [Gly529Arg]), which causes an amino acid change from Gly to Arg at position 529 that leads to mental retardation, autosomal dominant 39.


Assuntos
Deficiência Intelectual/etiologia , Mutação , Proteínas do Tecido Nervoso/genética , Obesidade/etiologia , Fatores de Transcrição/genética , Idade de Início , Feminino , Humanos , Recém-Nascido , Deficiência Intelectual/patologia , Obesidade/patologia , Prognóstico
4.
Dev Neurobiol ; 79(1): 85-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30548231

RESUMO

Since the first observation that described a patient with a mutation in IL1RAPL1 gene associated with intellectual disability in 1999, the function of IL1RAPL1 has been extensively studied by a number of laboratories. In this review, we summarize all the major data describing the synaptic and neuronal functions of IL1RAPL1 and recapitulate most of the genetic deletion identified in humans and associated to intellectual disability (ID) and autism spectrum disorders (ASD). All the data clearly demonstrate that IL1RAPL1 is a synaptic adhesion molecule localized at the postsynaptic membrane. Mutations in IL1RAPL1 gene cause either the absence of the protein or the production of a dysfunctional protein. More recently it has been demonstrated that IL1RAPL1 regulated dendrite formation and mediates the activity of IL-1ß on dendrite morphology. All these data will possibly contribute to identifying therapies for patients carrying mutations in IL1RAPL1 gene.


Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Proteína Acessória do Receptor de Interleucina-1/genética , Mutação/genética , Animais , Transtorno do Espectro Autista/patologia , Humanos , Deficiência Intelectual/patologia , Neurônios/patologia , Sinapses/patologia
5.
J Hum Genet ; 64(3): 253-255, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30542208

RESUMO

In view of conflicting reports on the pathogenicity of 15q11.2 CNVs of the breakpoints 1-2 (BP1-BP2) region and lack of association with a specific phenotype, we collected phenotypic data on 51,462 patients referred for genetic testing at two centers (Magee-Womens Hospital of UPMC and Baylor Genetics Laboratories, Baylor College of Medicine). Using array CGH, 262 patients with deletions and 215 with duplications were identified and tested for their association with four phenotypes (developmental delay, dysmorphic features, autism group of disorders, and epilepsy/seizures). Only association of deletions with dysmorphic features was observed (P = 0.013) with low penetrance (3.8%). Our results, viewed in the context of other reports suggesting the lack of a clear phenotypic outcome, underscore the need for detailed phenotypic studies to better understand the pathogenicity of 15q11.2 (BP1-BP2) CNVs.


Assuntos
Transtorno Autístico/genética , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 15/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Transtorno Autístico/patologia , Estudos de Coortes , Deficiências do Desenvolvimento/patologia , Epilepsia/patologia , Humanos , Deficiência Intelectual/patologia , Fenótipo
6.
Mol Genet Genomic Med ; 7(2): e00496, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565424

RESUMO

BACKGROUND: Chromothripsis, which is the local massive shattering of one or more chromosomes and their reassembly in a disordered array with frequent loss of some fragments, has been mainly reported in association with abnormal phenotypes. We report three unrelated healthy persons, two of which parenting a child with some degree of intellectual disability, carrying a chromothripsis involving respectively one, two, and three chromosomes, which was detected only after whole-genome sequencing. Unexpectedly, in all three cases a fragment from one of the chromothripsed chromosomes resulted to be inserted within a nonchromothripsed one. METHODS: Conventional cytogenetic techniques, paired-end whole-genome sequencing, polymerase chain reaction, and Sanger sequencing were used to characterize complex rearrangements, copy-number variations, and breakpoint sequences in all three families. RESULTS: In two families, one parent was carrier of a balanced chromothripsis causing in the index case a deletion and a noncontiguous duplication at 3q in case 1, and a t(6;14) translocation associated with interstitial 14q deletion in case 2. In the third family, an unbalanced chromothripsis involving chromosomes 6, 7, and 15 was inherited to the proband by the mosaic parent. In all three parents, the chromothripsis was concurrent with an insertional translocation of a portion of one of the chromothriptic chromosomes within a further chromosome that was not involved in the chromothripsis event. CONCLUSION: Our findings show that (a) both simple and complex unbalanced rearrangements may result by the recombination of a cryptic parental balanced chromothripsis and that (b) insertional translocations are the spy of more complex rearrangements and not simply a three-breakpoint event.


Assuntos
Cromotripsia , Deficiência Intelectual/genética , Adolescente , Criança , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Translocação Genética
7.
Autops. Case Rep ; 8(3): e2018031, July-Sept. 2018. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-911906

RESUMO

Snyder-Robinson syndrome, also known as spermine synthase deficiency, is an X-linked intellectual disability syndrome (OMIM #390583). First described by Drs. Snyder and Robinson in 1969, this syndrome is characterized by an asthenic body habitus, facial dysmorphism, broad-based gait, and osteoporosis with frequent fractures. We report here a pediatric autopsy of a 4 year old male with a history of intellectual disability, gait abnormalities, multiple fractures, and seizures previously diagnosed with Snyder-Robinson syndrome with an SMS gene mutation (c.831G>T:p.L277F). The cause of death was hypoxic-ischemic encephalopathy secondary to prolonged seizure activity. Although Snyder-Robinson syndrome is rare, the need to recognize clinical findings in order to trigger genetic testing has likely resulted in under diagnosis.


Assuntos
Humanos , Masculino , Pré-Escolar , Retardo Mental Ligado ao Cromossomo X/patologia , Autopsia , Evolução Fatal , Hipóxia-Isquemia Encefálica/patologia , Deficiência Intelectual/patologia , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Convulsões/patologia , Espermina Sintase
8.
Hum Genet ; 137(9): 717-721, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30097719

RESUMO

Intellectual disability (ID) is a severe neurodevelopmental disorder with genetically heterogeneous causes. Large-scale sequencing has led to the identification of many gene-disrupting mutations; however, a substantial proportion of cases lack a molecular diagnosis. As such, there remains much to uncover for a complete understanding of the genetic underpinnings of ID. Genetic variants present in non-coding regions of the genome have been highlighted as potential contributors to neurodevelopmental disorders given their role in regulating gene expression. Nevertheless the functional characterization of non-coding variants remains challenging. We describe the identification and characterization of de novo non-coding variation in 3'UTR regulatory regions within an ID cohort of 50 patients. This cohort was previously screened for structural and coding pathogenic variants via CNV, whole exome and whole genome analysis. We identified 44 high-confidence single nucleotide non-coding variants within the 3'UTR regions of these 50 genomes. Four of these variants were located within predicted miRNA binding sites and were thus hypothesised to have regulatory consequences. Functional testing showed that two of the variants interfered with miRNA-mediated regulation of their target genes, AMD1 and FAIM. Both these variants were found in the same individual and their functional consequences may point to a potential role for such variants in intellectual disability.


Assuntos
Regiões 3' não Traduzidas/genética , Regulação da Expressão Gênica , Variação Genética , Genoma Humano , Deficiência Intelectual/genética , Estudos de Coortes , Humanos , Deficiência Intelectual/patologia , MicroRNAs , Análise de Sequência de DNA/métodos
9.
Proc Natl Acad Sci U S A ; 115(28): E6640-E6649, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946028

RESUMO

Endosomes have emerged as a central hub and pathogenic driver of Alzheimer's disease (AD). The earliest brain cytopathology in neurodegeneration, occurring decades before amyloid plaques and cognitive decline, is an expansion in the size and number of endosomal compartments. The strongest genetic risk factor for sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4). Previous studies have shown that ApoE4 potentiates presymptomatic endosomal dysfunction and defective endocytic clearance of amyloid beta (Aß), although how these two pathways are linked at a cellular and mechanistic level has been unclear. Here, we show that aberrant endosomal acidification in ApoE4 astrocytes traps the low-density lipoprotein receptor-related protein (LRP1) within intracellular compartments, leading to loss of surface expression and Aß clearance. Pathological endosome acidification is caused by ε4 risk allele-selective down-regulation of the Na+/H+ exchanger isoform NHE6, which functions as a critical leak pathway for endosomal protons. In vivo, the NHE6 knockout (NHE6KO) mouse model showed elevated Aß in the brain, consistent with a causal effect. Increased nuclear translocation of histone deacetylase 4 (HDAC4) in ApoE4 astrocytes, compared with the nonpathogenic ApoE3 allele, suggested a mechanistic basis for transcriptional down-regulation of NHE6. HDAC inhibitors that restored NHE6 expression normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking, and amyloid clearance. Thus, NHE6 is a downstream effector of ApoE4 and emerges as a promising therapeutic target in AD. These observations have prognostic implications for patients who have Christianson syndrome with loss of function mutations in NHE6 and exhibit prominent glial pathology and progressive hallmarks of neurodegeneration.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Astrócitos/metabolismo , Endossomos/metabolismo , Epigênese Genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Apolipoproteína E4/genética , Astrócitos/patologia , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/metabolismo , Ataxia/patologia , Endossomos/genética , Endossomos/patologia , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Camundongos , Camundongos Knockout , Microcefalia/tratamento farmacológico , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/patologia , Transtornos da Motilidade Ocular/tratamento farmacológico , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/metabolismo , Transtornos da Motilidade Ocular/patologia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
10.
J Radiol Case Rep ; 12(3): 18-27, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29875990

RESUMO

We report the imaging appearances of a case of pathologically proven, neonatal neuroblastoma 4S with diffuse hepatic metastatic involvement at presentation. Patient had an abnormal appearing liver both by ultrasound and MR. There was no evidence for associated adrenal tumor by imaging. Lack of an associated adrenal mass led to initial misinterpretation of diffuse hepatic accumulation of MIBG seen with radionuclide scintigraphy. To the best our knowledge, this is the first report of metastatic neonatal 4S neuroblastoma without an adrenal (or extra-adrenal) primary identified either on pre- or post-natal imaging.


Assuntos
Neoplasias Encefálicas/patologia , Dedos/anormalidades , Deficiência Intelectual/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Microcefalia/patologia , Hipotonia Muscular/patologia , Miopia/patologia , Neuroblastoma/secundário , Obesidade/patologia , 3-Iodobenzilguanidina , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/análise , Biópsia , Neoplasias Encefálicas/tratamento farmacológico , Meios de Contraste , Deficiências do Desenvolvimento/patologia , Diagnóstico Diferencial , Feminino , Dedos/patologia , Humanos , Recém-Nascido , Neoplasias Hepáticas/tratamento farmacológico , Imagem por Ressonância Magnética , Estadiamento de Neoplasias , Neuroblastoma/tratamento farmacológico , Compostos Organometálicos , Degeneração Retiniana , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X
12.
Brain Dev ; 40(9): 760-767, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29803542

RESUMO

OBJECTIVE: To reveal a molecular lesion in the ZC4H2 gene in a Japanese family with arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), and to characterize clinical features of patients with ZC4H2 gene mutations through a literature review. PATIENTS: The probands are male siblings. The elder brother is an 11-year-old boy who showed AMC and ID and frequent postprandial hypoglycemia since 3 years of age. The younger brother also showed AMC, ID, and subclinical postprandial hypoglycemia. The boys' mother also showed a minor malformation of the left toes. METHOD AND RESULT: Using Sanger sequencing, a hemizygous one base substitution designated c.627G > C, which is predicted to substitute asparagine for lysine at amino acid residue 209 (K209N), was identified in the siblings. The mother was heterozygous for this mutation. In silico analysis predicted K209N to be a constituent of a motif required for subcellular localization of the ZC4H2 protein in the nucleus. Transient expression studies of subcellular localization in COS-7 cells showed that compared to the wild-type protein, the transport of the mutant protein into the nucleus was inhibited, thus confirming K209N as a molecular lesion in this family. The literature reviews revealed postprandial hypoglycemia as a new clinical feature that should be considered in ZC4H2 gene-mutation disorders. CONCLUSION: A Japanese family with AMC and ID caused by a novel ZC4H2 gene mutation was reported. Hypoglycemia should be considered one of the features in this disorder.


Assuntos
Artrogripose/genética , Proteínas de Transporte/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Artrogripose/patologia , Artrogripose/fisiopatologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Criança , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Irmãos
13.
Seizure ; 59: 38-40, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29734022

RESUMO

Terminal deletions of long arm of chromosome 13 are rare and poorly characterized by cytogenetic studies, making for difficult genotype-phenotype correlations. We report two siblings presenting generalized epilepsy, intellectual disability, and genitourinary tract defects. Array CGH detected a 1.3 Mb deletion at 13q34; it contains two protein-coding genes, SOX1 and ARHGEF7, whose haploinsufficiency can contribute to the epileptic phenotype.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13 , Epilepsia Generalizada/genética , Deficiência Intelectual/genética , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Criança , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/patologia , Epilepsia Generalizada/fisiopatologia , Face/anormalidades , Humanos , Lactente , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Transcrição SOXB1/genética , Irmãos
14.
Nat Commun ; 9(1): 1352, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29636449

RESUMO

Feingold syndrome is a skeletal dysplasia caused by loss-of-function mutations of either MYCN (type 1) or MIR17HG that encodes miR-17-92 microRNAs (type 2). Since miR-17-92 expression is transcriptionally regulated by MYC transcription factors, it has been postulated that Feingold syndrome type 1 and 2 may be caused by a common molecular mechanism. Here we show that Mir17-92 deficiency upregulates TGF-ß signaling, whereas Mycn-deficiency downregulates PI3K signaling in limb mesenchymal cells. Genetic or pharmacological inhibition of TGF-ß signaling efficiently rescues the skeletal defects caused by Mir17-92 deficiency, suggesting that upregulation of TGF-ß signaling is responsible for the skeletal defect of Feingold syndrome type 2. By contrast, the skeletal phenotype of Mycn-deficiency is partially rescued by Pten heterozygosity, but not by TGF-ß inhibition. These results strongly suggest that despite the phenotypical similarity, distinct molecular mechanisms underlie the pathoetiology for Feingold syndrome type 1 and 2.


Assuntos
Pálpebras/anormalidades , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , MicroRNAs/genética , Microcefalia/genética , Proteína Proto-Oncogênica N-Myc/genética , Transdução de Sinais/genética , Fístula Traqueoesofágica/genética , Animais , Modelos Animais de Doenças , Pálpebras/metabolismo , Pálpebras/patologia , Feminino , Regulação da Expressão Gênica , Heterozigoto , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Deformidades Congênitas dos Membros/metabolismo , Deformidades Congênitas dos Membros/patologia , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Microcefalia/metabolismo , Microcefalia/patologia , Proteína Proto-Oncogênica N-Myc/deficiência , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fístula Traqueoesofágica/metabolismo , Fístula Traqueoesofágica/patologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
15.
J Genet ; 97(1): 205-211, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29666339

RESUMO

Emanuel syndrome is caused due to an additional derivative chromosome 22 and is characterized by severe intellectual disability, microcephaly, failure to thrive, preauricular tags or pits, ear anomalies, cleft or high-arched palate, micrognathia, kidney abnormalities, congenital heart defects and genital abnormalities in males. In 99% of the cases, one of the parents is a carrier of balanced translocation between chromosomes 11 and 22. It occurs due to malsegregation of the gametes with 3:1 segregation. In this case series, we describe four patients with diverse manifestations of this condition. The craniosynostosis observed in one case is a novel finding which has never been reported previously. This study aims to widen the phenotypic spectrum of Emanuel syndrome and provide cytogenetic microarray based breakpoints in two of the cases, thus supporting close clustering of the breakpoints of this common recurrent chromosomal rearrangement.


Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Fissura Palatina/genética , Fissura Palatina/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Criança , Transtornos Cromossômicos/diagnóstico por imagem , Fissura Palatina/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Cariotipagem , Masculino , Hipotonia Muscular/diagnóstico por imagem , Fenótipo
16.
Gene ; 660: 13-17, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29572195

RESUMO

Biallelic UNC80 mutations cause infantile hypotonia with psychomotor retardation and characteristic facies 2 (IHPRF2), which is characterized by hypotonia, developmental delay (DD)/intellectual disability (ID), intrauterine growth retardation, postnatal growth retardation and characteristic facial features. We report two unrelated Chinese patients with compound heterozygous UNC80 mutations inherited from their parents, as identified by whole-exome sequencing (WES). Mutations c.3719G>A (p.W1240*)/c.4926_4937del (p.N1643_L1646del) and c.4963C>T (p.R1655C)/c.8385C>G (p.Y2795*) were identified in patient 1 and patient 2, respectively. Although both patients presented with DD/ID and hypotonia, different manifestations also occurred. Patient 1 presented with infantile hypotonia, epilepsy and hyperactivity without growth retardation, whereas patient 2 presented with persistent hypotonia, growth retardation and self-injury without epilepsy. Furthermore, we herein summarize the genotypes and phenotypes of patients with UNC80 mutations reported in the literature, revealing that IHPRF2 is a phenotypically heterogeneous disease. Common facial dysmorphisms include a thin upper lip, a tented upper lip, a triangular face, strabismus and microcephaly. To some extent, the manifestations of IHPRF2 mimic those of Angelman syndrome (AS)-like syndromes.


Assuntos
Anormalidades Múltiplas , Alelos , Proteínas de Transporte/genética , Deficiência Intelectual , Proteínas de Membrana/genética , Hipotonia Muscular , Mutação , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Grupo com Ancestrais do Continente Asiático , Criança , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/genética , Hipotonia Muscular/patologia
17.
Histochem Cell Biol ; 149(6): 593-605, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29574488

RESUMO

The Simpson-Golabi-Behmel syndrome (SGBS) cell strain is widely considered to be a representative in vitro model of human subcutaneous white pre-adipocytes. These cells achieve a transient expression of classical brown markers, such as uncoupling protein 1, peaking at day 14 of differentiation and decreasing thereafter. Adipocyte browning process involves dynamic changes in lipid droplet (LD) dimension, in mitochondria morphology, and in the expression of brown-specific marker genes. This study analyzes SGBS transient phenotypic transformation by quantifying the heterogeneity of LDs, mitochondrial dynamics, and a panel of genes involved in adipocyte differentiation and browning. LDs at 21 days of differentiation were larger than in the previous stages, without any change in the number per cell. The expression of genes such as peroxisome peroxisome proliferator-activated receptor γ, leptin, and lipase E significantly raised from 0 to 21 days. Adiponectin was significantly upregulated at 14 days of differentiation. Brown-specific marker PR domain containing 16 was highly expressed at D0. The variability of mitochondrial shape and interconnectivity reflects differences in the relative rates of fusion and fission, resulting in a significant shift from a networked shape at D7 to a fragmented and swollen one at D14 and D21. The transient phenotype experienced by this cellular model should be considered whether used in studies involving the stimulation of adipocyte browning and could be an interesting human model to further elucidate the browning process in the absence of any stimulation.


Assuntos
Adipócitos/patologia , Arritmias Cardíacas/patologia , Diferenciação Celular , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Deficiência Intelectual/patologia , Adipócitos/metabolismo , Arritmias Cardíacas/metabolismo , Células Cultivadas , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Gigantismo/metabolismo , Cardiopatias Congênitas/metabolismo , Humanos , Deficiência Intelectual/metabolismo , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fenótipo
18.
J Pediatr Endocrinol Metab ; 31(5): 581-584, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29494340

RESUMO

Backgorund: Sanjad-Sakati syndrome (SSS) is a rare autosomal recessive disease caused by a deletion mutation (155-166del) in exon 3 of the TBCE gene on chromosome 1q42-43. The syndrome is characterized by primary hypoparathyroidism, typical dysmorphic features and severe growth retardation. CASE PRESENTATION: We encountered a 2-year-old boy with hypocalcemia, failure to thrive and macrocytic anemia. The patient had the characteristic features of SSS and genetic testing confirmed that he was homozygous for the TBCE mutation. Although malabsorption was initially considered the cause of his symptoms, the results did not confirm that diagnosis. Our patient had cow milk protein allergy and folic acid deficiency, which has not been described in previous SSS cases. It was difficult to treat the patient's hyperphosphatemia and we ultimately selected sevelamer treatment, which was tolerated well and improved his hypocalcemia. CONCLUSIONS: SSS should be considered in the differential diagnosis of any infant with hypocalcemia, dysmorphism and failure to thrive.


Assuntos
Anemia Macrocítica/complicações , Insuficiência de Crescimento/etiologia , Transtornos do Crescimento/complicações , Hipoparatireoidismo/complicações , Deficiência Intelectual/complicações , Osteocondrodisplasias/complicações , Convulsões/complicações , Anormalidades Múltiplas/patologia , Anemia Macrocítica/patologia , Pré-Escolar , Transtornos do Crescimento/patologia , Humanos , Hipoparatireoidismo/patologia , Deficiência Intelectual/patologia , Masculino , Osteocondrodisplasias/patologia , Prognóstico , Convulsões/patologia
19.
Gene ; 655: 65-70, 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-29477873

RESUMO

Lamb-Shaffer syndrome (OMIM: 616803) is a neurodevelopmental disorder characterized by developmental delay, mild to moderate intellectual disability, speech delay, and mild characteristic facial appearance caused by SOX5 haploinsufficiency on chromosome 12p12.1. There are clinical variabilities among the patients with genomic alterations, such as intragenic deletions, a point mutation, and a chromosomal translocation of t(11;12)(p13;p12.1), in SOX5. We report herein a 5-year-old Japanese male with a de novo balanced reciprocal translocation t(12;20)(p12.1;p12.3) presenting a mild intellectual disability, speech delay, characteristic facial appearance, and autistic features. We determined the translocation breakpoints of the patient to be in intron 4 of SOX5 and the intergenic region in 20p12.3 via FISH and nucleotide sequence analyses. Thus, the present patient has SOX5 haploinsufficiency affecting 2 long forms of SOX5 and is the second reported case of Lamb-Shaffer syndrome caused by a de novo balanced reciprocal translocation. This report confirmed that haploinsufficiency of the 2 long forms of SOX5 presents common clinical features, including mild intellectual disability and autistic features, which could be useful for the clinical diagnosis of Lamb-Shaffer syndrome.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 20 , Haploinsuficiência , Fatores de Transcrição SOXD/genética , Translocação Genética , Transtorno Autístico/genética , Transtorno Autístico/patologia , Pré-Escolar , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 20/genética , Análise Mutacional de DNA , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino
20.
Eur J Med Genet ; 61(1): 29-33, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29038029

RESUMO

The TBL1XR1 gene product is a nuclear protein ubiquitously produced. The protein is a component of SMRT/N-CoR co-repressor complexes and participates in the molecular switch of specific gene transcription. Deletions of the TBL1XR1 gene have been described in two families to date, both presenting intellectual disability and dysmorphisms. Rare recurrent chromosomal micro-rearrangements, particularly those involving single genes, represent a challenge for clinicians to ensure correlation with phenotype due to the paucity of previously described cases. Here we present a patient harbouring a TBL1XR1 gene deletion detected by chromosome microarray analysis. In addition to intellectual disability, the patient presents dysmorphic features and multiple cardiac malformations, together with brain malformation, thus contributing to the phenotypic characterization of this rare microdeletion and to the TBL1XR1 gene function.


Assuntos
Encéfalo/anormalidades , Deleção de Genes , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Fenótipo , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Criança , Feminino , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/patologia , Síndrome
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