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1.
BMC Med Genet ; 20(1): 93, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146700

RESUMO

BACKGROUND: CHARGE syndrome is characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is the major cause of CHARGE syndrome and is inherited in an autosomal dominant manner. Currently, the phenotype spectrum of CHARGE syndrome in neonatal population remain elusive. We aimed to investigate the phenotype spectrum of neonatal patients suspected to have CHARGE syndrome with pathogenic or likely pathogenic variants in the CHD7 gene. METHODS: We pooled next-generation sequencing data from the Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov Identifier: NCT02551081) in Children's Hospital of Fudan University. The pathogenicity of novel variants was analyzed by bioinformatic and genetic analyses. Clinical information collection, Sanger sequencing and follow-up interviews were performed when possible. Cranial MRI of these patients was performed, the volumes of different regions of the brain were analyzed. RESULTS: A total of 12 unrelated patients in our cohort were found with CHD7 variants. Eight patients received a firm clinical diagnosis of CHARGE syndrome (Bergmann criteria, Blake criteria, Verloes criteria and Hale criteria). Three patients did not match any diagnostic criteria, and no patients matched the Verloes criteria. Phenotype spectrum analysis found that feeding difficulty was the dominant feature among this neonatal cohort. Six novel variants in the CHD7 gene (Glu2408*, Lys651*, c.5607 + 1G > T, Leu373Val, Lys2005Asnfs*37 and Gln1991*) were identified, expanding the variant database of the CHD7 gene. Cranial MRI analysis revealed significant volume loss in cingulate gyrus, occipital lobe, and cerebellum and volume gain in the left medial and inferior temporal gyri anterior white matter parts. CONCLUSIONS: Based on a relatively unbiased neonatal cohort, we concluded that CHARGE syndrome and CHD7 gene variants should be suspected in newborns who have feeding difficulty, and one or more malformations. TRIAL REGISTRATION: Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov identifier: NCT02551081 ).


Assuntos
Síndrome CHARGE/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Predisposição Genética para Doença/genética , Mutação , Grupo com Ancestrais do Continente Asiático/genética , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/etnologia , China , Estudos de Coortes , Transtornos da Alimentação e da Ingestão de Alimentos/diagnóstico , Transtornos da Alimentação e da Ingestão de Alimentos/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/métodos , Fenótipo , Curva ROC
4.
J Laryngol Otol ; 132(4): 329-335, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29335043

RESUMO

OBJECTIVES: To compare the outcomes of endoscopic repair of bilateral congenital choanal atresia using a flap technique without stenting versus endoscopic repair using stenting without a flap. METHODS: A prospective randomised controlled study was conducted, comprising 72 patients with bilateral congenital choanal atresia. The patients were randomised into two groups. Group A (42 patients) underwent endoscopic repair using a mirrored L-shaped flap without stenting, and group B (30 patients) underwent endoscopic repair using stenting without a flap. RESULTS: At a mean follow-up period of 18.2 months, endoscopic assessment revealed a patent posterior choana in 81 per cent and 83.33 per cent of patients in group A and group B respectively. Choanal stenosis occurred in 21.40 per cent and 33.33 per cent of patients in group A and group B respectively. Granulation tissue was observed in 28.6 per cent and 53.3 per cent of patients in group A and group B respectively. CONCLUSION: The endoscopic approach utilising a flap without stenting is safe and effective, with a high success rate.


Assuntos
Síndrome CHARGE/cirurgia , Atresia das Cóanas/cirurgia , Endoscopia/métodos , Cavidade Nasal/cirurgia , Retalhos Cirúrgicos/estatística & dados numéricos , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/epidemiologia , Atresia das Cóanas/diagnóstico , Atresia das Cóanas/epidemiologia , Anormalidades Congênitas , Feminino , Humanos , Recém-Nascido , Masculino , Cavidade Nasal/anormalidades , Lavagem Nasal/enfermagem , Avaliação de Resultados (Cuidados de Saúde) , Complicações Pós-Operatórias , Período Pós-Operatório , Estudos Prospectivos , Stents/estatística & dados numéricos , Retalhos Cirúrgicos/tendências , Tomografia Computadorizada por Raios X , Resultado do Tratamento
6.
Am J Med Genet C Semin Med Genet ; 175(4): 397-406, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29171162

RESUMO

CHARGE syndrome is a multiple congenital anomaly condition caused, in a majority of individuals, by loss of function pathogenic variants in the gene CHD7. In this special issue of the American Journal of Medical Genetics part C, authors of eleven manuscripts describe specific organ system features of CHARGE syndrome, with a focus on recent developments in diagnosis, etiologies, and treatments. Since 2004, when CHD7 was identified as the major causative gene in CHARGE, several animal models (mice, zebrafish, flies, and frog) and cell-based systems have been developed to explore the underlying pathophysiology of this condition. In this article, we summarize those advances, highlight opportunities for new discoveries, and encourage readers to explore specific organ systems in more detail in each individual article. We hope the excitement around innovative research and development in CHARGE syndrome will encourage others to join this effort, and will stimulate other investigators and professionals to engage with individuals diagnosed as having CHARGE syndrome, their families, and their care providers.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/etiologia , Síndrome CHARGE/terapia , Animais , Síndrome CHARGE/epidemiologia , Progressão da Doença , Humanos , Fenótipo , Prevalência , Pesquisa , Pesquisa Médica Translacional
7.
Am J Med Genet C Semin Med Genet ; 175(4): 407-416, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29088501

RESUMO

CHARGE syndrome (CS) is a complex genetic disorder causing multiple birth defects and sensory deficits (hearing, vision, balance, smell). Genetic counseling in CS must include not only the provision of factual information about CS, its cause, and inheritance, but also information about the developmental implications of CS features, referral to appropriate resources, and assistance with psychosocial adaptation to this information. CS should be considered in patients with any of the major diagnostic features: coloboma, choanal atresia, semicircular canal anomalies, or cranial nerve anomalies. The prime candidates in the differential are 22q11.2 deletion and Kabuki syndromes. Evaluation of features of CS, dysmorphology examination, and genetic testing can usually distinguish between the three conditions. Genetic counseling is important from early on, to help the family understand the process of genetic diagnosis, to interpret information coming from other specialists and to provide support and resources. Parents can easily be overwhelmed with the complexity of issues facing their child at diagnosis and in the future. CS is a substantial burden on a child, with high early mortality, multiple illnesses, hospitalizations and surgeries, and apparent medical fragility throughout life. The medical complexity of CS disrupts family life and contributes to delayed development. Multiple sensory deficits (impaired vision, hearing, and balance) further contribute to delayed motor and language development despite many individuals with CS having normal intelligence. Early referral to specialists in deafblindness and sensory deficits is essential. Resources are available to assist genetic counselors in diagnosis, follow-up, and management of patients with CS.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Aconselhamento Genético , Diagnóstico Diferencial , Gerenciamento Clínico , Seguimentos , Estudos de Associação Genética , Testes Genéticos , Humanos , Fenótipo , Prognóstico
8.
Am J Med Genet C Semin Med Genet ; 175(4): 487-495, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29088513

RESUMO

Heart defects caused by loss-of-function mutations in CHD7 are a frequent cause of morbidity and mortality in CHARGE syndrome. Here we review the clinical and molecular aspects of CHD7 that are related to the cardiovascular manifestations of the syndrome. The types of heart defects found in patients with CHD7 mutations are variable, with an overrepresentation of atrioventricular septal defect and outflow tract defect including aortic arch anomalies compared to nonsyndromic heart defects. Chd7 haploinsufficiency in mouse is a good model for studying the heart effects seen in CHARGE syndrome, and mouse models reveal a role for Chd7 in multiple lineages during heart development. Formation of the great vessels requires Chd7 expression in the pharyngeal surface ectoderm, and this expression likely has an non-autonomous effect on neural crest cells. In the cardiogenic mesoderm, Chd7 is required for atrioventricular cushion development and septation of the outflow tract. Emerging knowledge about the function of CHD7 in the heart indicates that it may act in concert with transcription factors such as TBX1 and SMADs to regulate genes such as p53 and the cardiac transcription factor NKX2.5.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Mutação , Fenótipo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Especificidade de Órgãos/genética , Organogênese/genética , Transdução de Sinais
9.
Am J Med Genet C Semin Med Genet ; 175(4): 507-515, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29152903

RESUMO

Mutations in the gene CHD7 cause CHARGE syndrome, a rare multi-organ syndromic disorder. Gonadal defects are common in individuals with CHARGE syndrome (seen in ∼60-80% of cases) and represent the letter "G" in the CHARGE syndrome acronym. The gonadal defect in CHARGE syndrome results from congenital deficiency of the hypothalamic hormone Gonadotropin-releasing hormone (GnRH), which manifests clinically as pubertal failure and infertility, and biochemically as hypogonadotropic hypogonadism (low sex steroid hormone levels with inappropriately normal or low gonadotropin levels). In addition to the gonadal endocrine abnormalities, in a small minority of individuals with CHARGE, additional endocrine defects including growth hormone deficiency, multiple pituitary hormone deficits and primary hypothyroidism may also be seen. CHD7 mutations disrupt the targeting of olfactory axons and the migration of GnRH-synthesizing neurons during embryonic development, resulting in congenital idiopathic hypogonadotropic hypogonadism (IHH) and anosmia (or hyposmia), two features that define human Kallmann syndrome. Since Kallmann syndrome is one of the constituent phenotypes within CHARGE, recent studies have investigated the role of CHD7 mutations in individuals with IHH and established that deleterious missense mutations in CHD7 are associated with Kallmann syndrome as well as normosmic form of IHH. These missense mutations affect the ATPase and nucleosome remodeling activities of the CHD7 protein. These observations suggest that CHD7 protein function is critical for the ontogeny of GnRH neurons and neuroendocrine regulation of GnRH secretion.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/genética , Genitália/anormalidades , Genitália/fisiopatologia , Mutação , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Animais , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Modelos Animais de Doenças , Estudos de Associação Genética , Humanos , Camundongos
10.
Am J Med Genet C Semin Med Genet ; 175(4): 516-523, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29159871

RESUMO

Immunodeficiency can occur in CHARGE syndrome, with immunophenotypes including reduction in T-cell counts, combined T-B cell defects rarely requiring antibiotic prophylaxis or immunoglobulin replacement, and severe combined immunodeficiency, which is fatal without immune reconstitution. However, the prevalence of immunodeficiency in CHARGE syndrome remains unclear with few prospective studies. In this review, we examine the existing literature covering immunodeficiency associated with CHARGE syndrome, compare these with immunodeficiencies reported in 22q11.2 deletion syndrome (a condition that shares many phenotypic characteristics with CHARGE syndrome) and suggest future research priorities.


Assuntos
Síndrome CHARGE/genética , Síndrome CHARGE/imunologia , Estudos de Associação Genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Fenótipo , Animais , Síndrome CHARGE/diagnóstico , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/metabolismo
11.
Am J Med Genet C Semin Med Genet ; 175(4): 450-464, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29168326

RESUMO

"CHARGE syndrome" is a complex syndrome with high and extremely variable comorbidity. As a result, clinicians may struggle to provide accurate and comprehensive care, and this has led to the publication of several clinical surveillance guidelines and recommendations for CHARGE syndrome, based on both single case observations and cohort studies. Here we perform a structured literature review to examine all the existing advice. Our findings provide additional support for the validity of the recently published Trider checklist. We also identified a gap in literature when reviewing all guidelines and recommendations, and we propose a guideline for neuroradiological evaluation of patients with CHARGE syndrome. This is of importance, as patients with CHARGE are at risk for peri-anesthetic complications, making recurrent imaging procedures under anesthesia a particular risk in clinical practice. However, comprehensive cranial imaging is also of tremendous value for timely diagnosis, proper treatment of symptoms and for further research into CHARGE syndrome. We hope the guideline for neuroradiological evaluation will help clinicians provide efficient and comprehensive care for individuals with CHARGE syndrome.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/terapia , Encéfalo/anormalidades , Síndrome CHARGE/genética , Gerenciamento Clínico , Humanos , Neuroimagem/métodos , Guias de Prática Clínica como Assunto
12.
Artigo em Inglês | MEDLINE | ID: mdl-29168327

RESUMO

Mutations in the gene encoding the ATP dependent chromatin-remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital-urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio-temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Cerebelo/anormalidades , Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Haploinsuficiência , Fenótipo , Animais , Biópsia , Cerebelo/patologia , Proteínas de Ligação a DNA/metabolismo , Deficiências do Desenvolvimento/diagnóstico , Modelos Animais de Doenças , Genótipo , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Imagem por Ressonância Magnética/métodos , Camundongos , Camundongos Transgênicos , Malformações do Sistema Nervoso/diagnóstico
13.
Am J Med Genet C Semin Med Genet ; 175(4): 417-430, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29178447

RESUMO

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Estudos de Associação Genética , Genótipo , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Sistema Nervoso Central/anormalidades , Criança , Pré-Escolar , Estudos de Coortes , Nervos Cranianos/anormalidades , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , França , Testes Genéticos , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Adulto Jovem
14.
Am J Med Genet C Semin Med Genet ; 175(4): 439-449, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29082607

RESUMO

The inner ear contains the sensory organs for hearing and balance. Both hearing and balance are commonly affected in individuals with CHARGE syndrome (CS), an autosomal dominant condition caused by heterozygous pathogenic variants in the CHD7 gene. Semicircular canal dysplasia or aplasia is the single most prevalent feature in individuals with CHARGE leading to deficient gross motor skills and ambulation. Identification of CHD7 as the major gene affected in CHARGE has enabled acceleration of research in this field. Great progress has been made in understanding the role of CHD7 in the development and function of the inner ear, as well as in related organs such as the middle ear and auditory and vestibular neural pathways. The goals of current research on CHD7 and CS are to (a) improve our understanding of the pathology caused by CHD7 pathogenic variants and (b) to provide better tools for prognosis and treatment. Current studies utilize cells and whole animals, from flies to mammals. The mouse is an excellent model for exploring mechanisms of Chd7 function in the ear, given the evolutionary conservation of ear structure, function, Chd7 expression, and similarity of mutant phenotypes between mice and humans. Newly recognized developmental functions for mouse Chd7 are shedding light on how abnormalities in CHD7 might lead to CS symptoms in humans. Here we review known human inner ear phenotypes associated with CHD7 pathogenic variants and CS, summarize progress toward diagnosis and treatment of inner ear-related pathologies, and explore new avenues for treatment based on basic science discoveries.


Assuntos
Síndrome CHARGE/diagnóstico , Orelha Interna/anormalidades , Orelha Interna/fisiopatologia , Animais , Síndrome CHARGE/genética , Síndrome CHARGE/terapia , Implantes Cocleares , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Gerenciamento Clínico , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Auxiliares de Audição , Humanos , Imagem por Ressonância Magnética , Camundongos , Mutação , Neurogênese , Fenótipo , Tomografia Computadorizada por Raios X
15.
Am J Med Genet C Semin Med Genet ; 175(4): 431-438, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29082623

RESUMO

Unusual behavior is often associated with genetic syndromes, and may constitute a behavioral phenotype. In contrast to providing a psychiatric diagnosis, a behavioral phenotype describes what is unique to the behavior associated with different syndromes. While behaviors in CHARGE are as complex and variable as other aspects of the syndrome, there are some commonalities that raise the question of common sources for these behaviors. This article addresses how pain, sensory issues, and anxiety may impact the behavior of individuals with CHARGE syndrome, and how the development of self-regulation skills might help to mitigate some of the behaviors.


Assuntos
Sintomas Comportamentais , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/psicologia , Ansiedade , Síndrome CHARGE/genética , Humanos , Dor , Autocontrole , Transtornos das Sensações
16.
Am J Med Genet C Semin Med Genet ; 175(4): 478-486, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29082625

RESUMO

Neural crest cells are highly migratory pluripotent cells that give rise to diverse derivatives including cartilage, bone, smooth muscle, pigment, and endocrine cells as well as neurons and glia. Abnormalities in neural crest-derived tissues contribute to the etiology of CHARGE syndrome, a complex malformation disorder that encompasses clinical symptoms like coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. Mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene are causative of CHARGE syndrome and loss-of-function data in different model systems have firmly established a role of CHD7 in neural crest development. Here, we will summarize our current understanding of the function of CHD7 in neural crest development and discuss possible links of CHARGE syndrome to other developmental disorders.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/etiologia , Crista Neural/anormalidades , Fenótipo , Trifosfato de Adenosina/metabolismo , Animais , Síndrome CHARGE/metabolismo , Montagem e Desmontagem da Cromatina , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Humanos , Complexos Multiproteicos/metabolismo , Mutação , Ligação Proteica
17.
Am J Med Genet C Semin Med Genet ; 175(4): 496-506, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29082627

RESUMO

CHARGE syndrome is an autosomal dominant genetic condition that is primarily diagnosed based on clinical features, with genetic testing available for confirmation. The CHARGE mnemonic stands for some of the common characteristics: coloboma, heart defects, atresia/stenosis of the choanae, retardation of growth/development, genitourinary anomalies, and ear abnormalities (CHARGE). However, many of the common clinical features are not captured by this mnemonic, including cranial nerve dysfunction, considered by some to be one of the major diagnostic criteria. Over 90% of individuals experience feeding and gastrointestinal dysfunction, which carries great morbidity and mortality. The aim of this review is to examine the nature of gastrointestinal (GI) symptoms and feeding difficulties in CHARGE syndrome, focusing on their underlying pathology, associated investigations, and available treatment options. We also provide information on available tools (for parents, clinicians, and researchers) that are important additions to the lifelong healthcare management of every individual with CHARGE syndrome. We review how cranial nerve dysfunction is one of the most important characteristics underlying the pervasive GI and feeding dysfunction, and discuss the need for future research on gut innervation and motility in this genetic disorder.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/etiologia , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Trato Gastrointestinal/anormalidades , Trato Gastrointestinal/fisiopatologia , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Animais , Síndrome CHARGE/terapia , Doenças dos Nervos Cranianos/genética , Doenças dos Nervos Cranianos/fisiopatologia , Feminino , Motilidade Gastrointestinal/genética
18.
Am J Hum Genet ; 100(5): 773-788, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28475860

RESUMO

Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7LOF) and lysine (K) methyltransferase 2D (KMT2DLOF), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder. Genome-wide DNAm profiles in individuals with CHARGE and Kabuki syndromes with CHD7LOF or KMT2DLOF identified distinct sets of DNAm differences in each of the disorders, which were used to generate two unique, highly specific and sensitive DNAm signatures. These DNAm signatures were able to differentiate pathogenic mutations in these two genes from controls and from each other. Analysis of the DNAm targets in each gene-specific signature identified both common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes, as well as distinct gene targets. Our findings demonstrate how characterization of the epigenome can contribute to our understanding of disease pathophysiology for epigenetic disorders, paving the way for explorations of novel therapeutics.


Assuntos
Anormalidades Múltiplas/genética , Síndrome CHARGE/genética , Metilação de DNA , Epigênese Genética , Face/anormalidades , Doenças Hematológicas/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Síndrome CHARGE/diagnóstico , Linhagem Celular , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Genoma Humano , Doenças Hematológicas/diagnóstico , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Doenças Vestibulares/diagnóstico
19.
Tex Heart Inst J ; 44(2): 138-140, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28461801

RESUMO

A male neonate presented with CHARGE syndrome, a multiorgan genetic disorder involving the Coloboma of the eyes, congenital Heart defects, nasal choanal Atresia, growth and development Retardation, Genitourinary disorders, and Ear anomalies and deafness. Moreover, he had a rare case of vascular ring-consisting of a right aortic arch with retroesophageal brachiocephalic artery-combined with coarctation of the mid-aortic arch. He underwent both vascular ring and aortic arch repair at our institution. To our knowledge, this is the 4th documented case of this exceedingly rare type of aortic arch anomaly combined with aortic arch obstruction. Moreover, it is the first confirmed case of these combined disorders occurring in CHARGE syndrome. This report describes a truly rare case and reveals the limitations of echocardiography in detecting complex aortic arch anomalies while illustrating the benefits of advanced imaging prior to surgical intervention.


Assuntos
Anormalidades Múltiplas , Coartação Aórtica/complicações , Síndrome CHARGE/complicações , Anel Vascular/complicações , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/fisiopatologia , Coartação Aórtica/cirurgia , Aortografia/métodos , Síndrome CHARGE/diagnóstico , Angiografia por Tomografia Computadorizada , Humanos , Recém-Nascido , Masculino , Resultado do Tratamento , Anel Vascular/diagnóstico por imagem , Anel Vascular/fisiopatologia , Anel Vascular/cirurgia
20.
Am J Med Genet A ; 173(3): 684-691, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28160409

RESUMO

Health supervision and management considerations for individuals with CHARGE syndrome are often complex, and a comprehensive approach is essential. The Atlantic Canadian CHARGE syndrome team developed a checklist organized by body system and age to aid healthcare providers in their approach to the ongoing care of these individuals. The checklist was evaluated qualitatively using a modified Delphi method with widespread consultation from expert healthcare practitioners, parents, and individuals with CHARGE syndrome. These are the first comprehensive guidelines across the lifespan of CHARGE syndrome that suggest a consistent approach to medical surveillance, investigations, and management for the physician and the multi-disciplinary team caring for these individuals. We anticipate that these guidelines will provide improvements in care by preventing missed diagnoses, allowing for anticipatory counseling, and facilitating early referral for interventions and treatments. © 2017 Wiley Periodicals, Inc.


Assuntos
Síndrome CHARGE/diagnóstico , Lista de Checagem , Síndrome CHARGE/genética , Canadá , Aconselhamento , Gerenciamento Clínico , Feminino , Testes Genéticos , Humanos , Masculino , Monitorização Fisiológica , Mutação , Fenótipo , Encaminhamento e Consulta
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