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1.
Arch Dis Child ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481360

RESUMO

INTRODUCTION: Fetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential. METHODS: We reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service. RESULTS: Seven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10). CONCLUSIONS: This study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

3.
Clin Genet ; 96(1): 72-84, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31001818

RESUMO

Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate-to-severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non-ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex-dependent penetrance of CHD8 PTVs in humans.

4.
Am J Hum Genet ; 104(2): 246-259, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30661772

RESUMO

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.


Assuntos
Anormalidades Múltiplas/genética , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição SOXC/genética , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , Síndrome de Coffin-Lowry/genética , Estudos de Coortes , Sequência Conservada , DNA/genética , DNA/metabolismo , Feminino , Domínios HMG-Box/genética , Heterozigoto , Humanos , Masculino , Fatores de Transcrição SOXC/química , Fatores de Transcrição SOXC/metabolismo , Ativação Transcricional , Xenopus/anatomia & histologia , Xenopus/embriologia , Xenopus/genética
5.
Am J Med Genet A ; 170(11): 2835-2846, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27667800

RESUMO

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Deleção Cromossômica , Cromossomos Humanos Par 16 , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Masculino , Fenótipo , Proteínas Repressoras/genética
6.
Am J Hum Genet ; 99(2): 253-74, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27453576

RESUMO

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.


Assuntos
Proteínas de Transporte/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Transcrição Genética , Animais , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Córtex Cerebral/metabolismo , Montagem e Desmontagem da Cromatina/genética , Códon sem Sentido/genética , Transtornos Cognitivos/genética , Mutação da Fase de Leitura/genética , Hipocampo/metabolismo , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/psicologia , Masculino , Camundongos , Microcefalia/genética , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Fenótipo , Comportamento Social , Síndrome , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Transcriptoma
7.
Brain ; 139(Pt 4): 1036-44, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26917597

RESUMO

Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with 'early infantile epileptic encephalopathy'. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772*ter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediated decay, and we demonstrate that the mutation produces a truncated protein lacking the crucial C-terminal half of CCDC88A (girdin). To further investigate the possible role of CCDC88A in human neurodevelopment we re-examined the behaviour and neuroanatomy of Ccdc88a knockout pups. These mice had mesial-temporal lobe epilepsy, microcephaly and corpus callosum deficiency, and by postnatal Day 21, microcephaly; the mice died at an early age. As the mouse knockout phenotype mimics the human PEHO phenotype this suggests that loss of CCDC88A is a cause of the PEHO phenotype, and that CCDC88A is essential for multiple aspects of normal human neurodevelopment.


Assuntos
Edema Encefálico/diagnóstico , Edema Encefálico/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Proteínas de Transporte Vesicular/genética , Animais , Encéfalo/patologia , Criança , Feminino , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Linhagem
8.
PLoS One ; 10(6): e0131417, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26120850

RESUMO

Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.


Assuntos
Carboxipeptidase H/genética , Diabetes Mellitus Tipo 2/complicações , Deficiência Intelectual/complicações , Síndrome de Klinefelter/complicações , Mutação/genética , Obesidade Mórbida/complicações , Obesidade Mórbida/genética , Carboxipeptidase H/metabolismo , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Exoma/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Homozigoto , Humanos , Deficiência Intelectual/genética , Síndrome de Klinefelter/enzimologia , Síndrome de Klinefelter/genética , Masculino , Obesidade Mórbida/enzimologia , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
9.
Ultrasound ; 23(3): 181-5, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27433255

RESUMO

The finding of bilateral congenital cataracts in the fetus is rare. We report bilateral congenital cataracts detected during the routine second trimester anomaly scan, which subsequently were found to be associated with other congenital anomalies and the parents opted for a termination of pregnancy. At post-mortem, Muscle-Eye Brain disease or Walker-Warburg Syndrome was considered likely, which are autosomal recessive congenital muscular dystrophy disorders associated with cerebral, cerebellar, muscle and eye anomalies. On ultrasound, bilateral cataracts appear as echogenic, solid areas within the fetal orbits. The examination of the fetal face and orbits plays an important role in confirming fetal well-being antenatally. We propose that it should become a routine part of the structural survey of fetal anatomy during the obstetric anomaly scan. This is especially important in pregnancies previously affected by fetal cataracts or pregnancies at risk of rare genetic syndromes.

10.
Am J Hum Genet ; 94(4): 618-24, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24680889

RESUMO

To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations-four nonsense (c.1195A>T [p.Lys399(∗)], c.1333C>T [p.Arg445(∗)], c.1866C>G [p.Tyr622(∗)], and c.3001C>T [p.Arg1001(∗)]) and three frameshift (c.2177_2178del [p.Thr726Asnfs(∗)39], c.3771dup [p.Ser1258Glufs(∗)65], and c.3856del [p.Ser1286Leufs(∗)84])-were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 3 , Deficiência Intelectual/genética , Metiltransferases/genética , Mutação , Adolescente , Criança , Humanos , Masculino
11.
Am J Med Genet A ; 164A(2): 386-91, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24311407

RESUMO

Osteogenesis imperfecta (OI) type I is a hereditary disorder of connective tissue (HDCT) characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures from infancy. We present four examples of OI type I complicated by valvular heart disease and associated with tissue fragility. The diagnosis of a type I collagen disorder was confirmed by abnormal COL1A1 or COL1A2 gene sequencing. One patient was investigated with electrophoresis of collagens from cultured skin fibroblasts, showing structurally abnormal collagen type I, skin biopsy showed unusual histology and abnormal collagen fibril ultra-structure at electron microscopy. The combined clinical, surgical, histological, ultra-structural, and molecular genetic data suggest the type I collagen defect as contributory to cardiac valvular disease. The degree of tissue fragility experienced at cardiac surgery in these individuals, also reported in a small number of similar case reports, suggests that patients with OI type I need careful pre-operative assessment and consideration of the risks and benefits of cardiac surgery.


Assuntos
Osso e Ossos/patologia , Colágeno Tipo I/genética , Doenças das Valvas Cardíacas/etiologia , Doenças das Valvas Cardíacas/patologia , Mutação , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/genética , Adulto , Criança , Feminino , Doenças das Valvas Cardíacas/diagnóstico , Ventrículos do Coração/patologia , Humanos , Instabilidade Articular/diagnóstico , Instabilidade Articular/etiologia , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/diagnóstico , Linhagem , Esclera/anormalidades , Pele/patologia , Pele/ultraestrutura
15.
Am J Hum Genet ; 91(1): 146-51, 2012 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-22683086

RESUMO

Hyperphosphatasia with mental retardation syndrome (HPMRS), an autosomal-recessive form of intellectual disability characterized by facial dysmorphism, seizures, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia), was recently shown to be caused by mutations in PIGV, a member of the glycosylphosphatidylinositol (GPI)-anchor-synthesis pathway. However, not all individuals with HPMRS harbor mutations in this gene. By exome sequencing, we detected compound-heterozygous mutations in PIGO, a gene coding for a membrane protein of the same molecular pathway, in two siblings with HPMRS, and we then found by Sanger sequencing further mutations in another affected individual; these mutations cosegregated in the investigated families. The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced. Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS.


Assuntos
Fosfatase Alcalina/sangue , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Mutação , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Modelos Moleculares , Linhagem , Síndrome
16.
Am J Hum Genet ; 90(2): 290-4, 2012 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-22265017

RESUMO

Genitopatellar syndrome (GPS) is a rare disorder in which patellar aplasia or hypoplasia is associated with external genital anomalies and severe intellectual disability. Using an exome-sequencing approach, we identified de novo mutations of KAT6B in five individuals with GPS; a single nonsense variant and three frameshift indels, including a 4 bp deletion observed in two cases. All identified mutations are located within the terminal exon of the gene and are predicted to generate a truncated protein product lacking evolutionarily conserved domains. KAT6B encodes a member of the MYST family of histone acetyltranferases. We demonstrate a reduced level of both histone H3 and H4 acetylation in patient-derived cells suggesting that dysregulation of histone acetylation is a direct functional consequence of GPS alleles. These findings define the genetic basis of GPS and illustrate the complex role of the regulation of histone acetylation during development.


Assuntos
Histona Acetiltransferases/genética , Anormalidades Musculoesqueléticas/genética , Mutação , Anormalidades Urogenitais/genética , Acetilação , Alelos , Animais , Exoma , Éxons , Feminino , Histonas/metabolismo , Humanos , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Masculino , Camundongos , Anormalidades Musculoesqueléticas/enzimologia , Análise de Sequência de DNA/métodos , Anormalidades Urogenitais/enzimologia
17.
Am J Med Genet A ; 158A(1): 215-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22105938

RESUMO

Schwannomatosis is a recently delineated inherited condition that has clinical overlap with neurofibromatosis type 2 (NF2). Diagnostic criteria have been developed to distinguish schwannomatosis from NF2, but the existence of mosaic NF2, which may closely mimic schwannomatosis, makes even these criteria problematic. In particular, it is not clear why there is a relative sparing of the cranial nerves from schwannomas in schwannomatosis. We have identified two individuals with schwannomatosis and a unilateral vestibular schwannoma (VS), where a diagnosis of NF2 has been excluded. A third case with an identified SMARCB1 mutation was reported by two radiologists to have a VS, but this was later confirmed as a jugular schwannoma. These cases question whether the current exclusion of a VS from the clinical diagnosis of schwannomatosis is justified.


Assuntos
Neurilemoma/diagnóstico , Neurilemoma/genética , Neurofibromatoses/diagnóstico , Neurofibromatoses/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Adulto , Idoso , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Proteína SMARCB1 , Fatores de Transcrição/genética
18.
Hum Mutat ; 32(10): 1144-52, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21837767

RESUMO

Disease-causing mutations affecting either one of the transcription factor genes, PITX2 or FOXC1, have been previously identified in patients with Axenfeld-Rieger syndrome (AR). We identified a family who segregate novel mutations in both PITX2 (p.Ser233Leu) and FOXC1 (c.609delC). The most severely affected individual, who presented with an atypical phenotype of corneal opacification, lens extrusion, persistent hyperplastic primary vitreous (PHPV), and subsequent bilateral retinal detachment, inherited mutations in both genes, whereas the single heterozygous mutations caused mild AR phenotypes. This is the first report of such digenic inheritance. By analyzing cognate targets of each gene, we showed that FOXC1 and PITX2 can independently regulate their own and each other's target gene promoters and do not show synergistic action in vitro. Mutation in either gene caused reduced transcriptional activation to different extents on the FOXO1 and PLOD1 promoters, whereas both mutations in combination showed the lowest level of activation. These data show how the compensatory activity of one factor, when the other is impaired, may lessen the phenotypic impact of developmental anomalies, yet reduced activity of both transcription factors increased disease severity. This suggests an under-reported mechanism for phenotypic variability whereby single mutations cause mild AR phenotypes, whereas digenic inheritance increases phenotypic severity.


Assuntos
Anormalidades do Olho/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Mutação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adulto , Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/metabolismo , Segmento Anterior do Olho/patologia , Pré-Escolar , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Olho/patologia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Oftalmopatias Hereditárias , Feminino , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Índice de Gravidade de Doença , Ativação Transcricional
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