RESUMO
Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.
Assuntos
Transtorno do Espectro Autista/enzimologia , Endossomos/metabolismo , Deficiência Intelectual/enzimologia , Proteínas dos Microfilamentos/metabolismo , Ubiquitina Tiolesterase/fisiologia , Adolescente , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Retroalimentação Fisiológica , Feminino , Células HCT116 , Haploinsuficiência , Humanos , Hipotálamo/metabolismo , Deficiência Intelectual/genética , Masculino , Neurônios/enzimologia , Proteínas Nucleares/metabolismo , Transporte Proteico , Proteólise , Deleção de Sequência , Peptidase 7 Específica de Ubiquitina , UbiquitinaçãoRESUMO
BACKGROUND: Care homes have experienced a high number of coronavirus disease 2019 (COVID-19)-related deaths among residents since the onset of the pandemic. However, up to May 2020, there has been a lack of information about the extent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among residents and staff in care homes and limited testing in this setting. METHODS: Combined nose and throat swab testing for SARS-CoV-2 RNA was carried out in 2455 residents and staff across 37 care homes in the London Borough of Bromley across a 3-week period. Results were reported within 24 hours of sample delivery, and data were collected on the presence or absence of symptoms. RESULTS: Overall, the point prevalence of SARS-CoV-2 infection was 6.5%, with a higher rate in residents (9.0%) than in staff (4.7%). A key finding was the high proportion of asymptomatic infection detected in staff (69%) and residents (51%), with evidence of underdetection of symptoms by care home staff. CONCLUSIONS: The high proportion of asymptomatic infection combined with underdetection of symptoms by care home staff indicates that offering a test to all residents and staff in care homes with rapid reporting of results would assist accurate identification of infected individuals, facilitating prompt infection prevention and control action.
Assuntos
COVID-19/virologia , Instituição de Longa Permanência para Idosos/estatística & dados numéricos , RNA Viral/genética , SARS-CoV-2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções Assintomáticas/epidemiologia , COVID-19/diagnóstico , COVID-19/epidemiologia , Teste para COVID-19/métodos , Feminino , Humanos , Londres/epidemiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Prevalência , RNA Viral/isolamento & purificação , SARS-CoV-2/isolamento & purificação , Adulto JovemRESUMO
Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.
Assuntos
Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Estudos de Associação Genética , Histona Desacetilases/genética , Fenótipo , Proteínas Repressoras/genética , Deleção de Sequência , Sequência de Bases , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Éxons , Fácies , Feminino , Duplicação Gênica , Humanos , Análise de Sequência de DNA , Inativação do Cromossomo XRESUMO
Cornelia de Lange Syndrome (CdLS) is due to mutations in the genes for the structural and regulatory proteins that make up the cohesin complex, and is considered a cohesinopathy disorder or, more recently, a transcriptomopathy. New phenotypes have been recognized in this expanding field. There are multiple clinical issues facing individuals with all forms of CdLS, particularly in the neurodevelopmental system, but also gastrointestinal, cardiac, and musculoskeletal. Aspects of developmental and cell biology have found common endpoints in the biology of the cohesin complex, with improved understanding of the mechanisms, easier diagnostic tests, and the possibility of potential therapeutics, all major clinical implications for the individual with CdLS. The following abstracts are the presentations from the 7th Cornelia de Lange Syndrome Scientific and Educational Symposium, June 22-23, 2016, in Orlando, FL, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting. In addition to the scientific and clinical discussions, there were talks related to practical aspects of behavior including autism, transitions, communication, access to medical care, and databases. At the end of the symposium, a panel was held, which included several parents, affected individuals and genetic counselors, and discussed the greatest challenges in life and how this information can assist in guiding future research. The Research Committee of the CdLS Foundation organizes this meeting, reviews, and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board and publications. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/fisiopatologia , Síndrome de Cornélia de Lange/diagnóstico , Humanos , Fenótipo , CoesinasRESUMO
SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/genética , Proteínas/genética , Síndrome de Rett/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/fisiopatologia , Exoma/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Síndrome de Rett/diagnóstico , Síndrome de Rett/fisiopatologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Adulto JovemRESUMO
We report on a 4-year-old female who presented with unilateral sensorineural hearing loss and a concern for developmental delay. A genome-wide SNP array analysis was performed and revealed a de novo 3.2 Mb interstitial deletion of chromosome 7q31.2q31.31. This region contains thirteen protein-encoding genes. It is unknown whether haploinsufficiency of any of these genes is responsible for the clinical features of our patient. We reviewed, the clinical phenotype of a previously published 7q31.3 deletion patient and 18 additional patients with overlapping 7q31 deletions listed in the DECIPHER database. The most consistent feature in these patients and our proband is delayed speech and language development. Hearing loss is presented both in our proband and the published 7q31.3 patient. Our study suggests that a small region on chromosome 7q31.3 encompassing four genes, CFTR, CTTNBP2, NAA38, and ANKRD7, may represent a new locus for congenital hearing loss and/or speech development. © 2016 Wiley Periodicals, Inc.
Assuntos
Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Transporte/genética , Pré-Escolar , Cromossomos Humanos Par 7/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Genoma Humano , Humanos , Proteínas de Membrana Transportadoras , Acetiltransferase N-Terminal C/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Ribonucleoproteína Nuclear Pequena U4-U6/genéticaRESUMO
This report describes a male child with a history of poor feeding and swallowing problems, hypotonia, mild bilateral sensorineural hearing loss, cerebral cortical agenesis, cardiac defects, cyanotic episodes triggered by specific movement, dysmorphic features, and developmental delays. Analysis by CytoScan HD array identified a 12.1 Mb interstitial deletion of 7q22.1q31.1 (98,779,628-110,868,171). We present a comprehensive review of the literature surrounding intermediate 7q deletions that overlap with this child's deletion, and an analysis of candidate genes in the deleted region. © 2016 Wiley Periodicals, Inc.
Assuntos
Anormalidades Múltiplas/genética , Encéfalo/anormalidades , Deleção Cromossômica , Criança , Cromossomos Humanos Par 7/genética , Deficiências do Desenvolvimento/genética , Fácies , Humanos , Masculino , Atrofia Muscular/genéticaRESUMO
There is an abundance of information in the literature on patient experiences with Internet support groups (ISGs). However, studies exploring these experiences in a rare disease population are scarce, even though these families are often at a disadvantage for resources, reliable information, and support. The aim of the current study was to explore the experiences with ISGs for parents of children with Cornelia de Lange syndrome (CdLS), a rare genetic diagnosis, in order to better understand the impact on emotional support and their child's medical care. Focus groups were conducted to inform the design of a large-scale internet survey. The survey asked parents closed- and open-ended questions regarding experiences with ISGs, with a focus on the psychosocial, medical, and logistical aspects. The survey found that 141/170 (82.6%) respondents have visited an Internet-based support group to find support or information about their child's CdLS diagnosis. The majority of respondents (71.7%) reported that ISGs have been helpful in finding emotional support, with the most common areas impacted as a result of ISG participation being behavior toward their children and family dynamic. Regarding medical care, most respondents (63.9%) reported that ISGs have been helpful in finding medical information and support, with the most commonly impacted areas of their child's care including day-to-day management, diet, therapy interventions, and healthcare providers. These findings provide a greater understanding of the role of Internet networking in healthcare and may inform future approaches to medical care and psychosocial support for rare, complex genetic diagnoses. © 2016 Wiley Periodicals, Inc.
Assuntos
Síndrome de Cornélia de Lange/psicologia , Grupos de Autoajuda , Atitude , Criança , Humanos , Internet , Pais , Inquéritos e QuestionáriosRESUMO
Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous multisystem developmental disorder with a high degree of variability in its clinical presentation. Approximately 65% of probands harbor mutations in genes that encode core components (SMC1A, SMC3, and RAD21) or regulators (NIPBL, HDAC8) of the cohesin complex, of which mutations in NIPBL are the most common. Cohesin plays a canonical role in sister chromatid cohesion during cell division and non-canonical roles in DNA repair, stem cell maintenance and differentiation, and regulation of gene expression. Disruption of the latter role seems to be the major contributor to the underlying molecular pathogenesis of CdLS. NIPBL is required for loading and unloading the cohesin complex onto chromosomes. The expression levels of NIPBL itself appear to be tightly regulated and highly evolutionarily conserved. Droplet digital PCR was used to quantify NIPBL mRNA expression levels with high precision from a cohort of 37 samples (NIPBL, SMC1A, SMC3, and HDAC8 mutation positive probands and negative control). Probands with severe forms of CdLS or severe mutation types were found to have lower levels of NIPBL in comparison to phenotypically milder patients and controls. Levels of NIPBL also correlated with the presence of mutations in different CdLS-causing genes. The data suggests that NIPBL levels are closely correlated with the severity of CdLS and with specific causative genes and types of mutations. ddPCR may provide a tool to assist in diagnostic approaches to CdLS, for genetic counseling and prognosis, and for monitoring potential therapeutic modalities in the future. © 2016 Wiley Periodicals, Inc.
Assuntos
Síndrome de Cornélia de Lange/patologia , Proteínas/genética , Proteínas de Ciclo Celular , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Mutação , Fenótipo , Reação em Cadeia da Polimerase , Proteínas/análise , Índice de Gravidade de DoençaRESUMO
Given the clinical complexities of Cornelia de Lange Syndrome (CdLS), the Center for CdLS and Related Diagnoses at The Children's Hospital of Philadelphia (CHOP) and The Multidisciplinary Clinic for Adolescents and Adults at Greater Baltimore Medical Center (GBMC) were established to develop a comprehensive approach to clinical management and research issues relevant to CdLS. Little work has been done to evaluate the general utility of a multispecialty approach to patient care. Previous research demonstrates several advantages and disadvantages of multispecialty care. This research aims to better understand the benefits and limitations of a multidisciplinary clinic setting for individuals with CdLS and related diagnoses. Parents of children with CdLS and related diagnoses who have visited a multidisciplinary clinic (N = 52) and who have not visited a multidisciplinary clinic (N = 69) were surveyed to investigate their attitudes. About 90.0% of multispecialty clinic attendees indicated a preference for multidisciplinary care. However, some respondents cited a need for additional clinic services including more opportunity to meet with other specialists (N = 20), such as behavioral health, and increased information about research studies (N = 15). Travel distance and expenses often prevented families' multidisciplinary clinic attendance (N = 41 and N = 35, respectively). Despite identified limitations, these findings contribute to the evidence demonstrating the utility of a multispecialty approach to patient care. This approach ultimately has the potential to not just improve healthcare for individuals with CdLS but for those with medically complex diagnoses in general. © 2016 Wiley Periodicals, Inc.
Assuntos
Síndrome de Cornélia de Lange/terapia , Comunicação Interdisciplinar , Medicina/organização & administração , Medicina de Precisão , Humanos , Pais , Inquéritos e QuestionáriosRESUMO
Cornelia de Lange syndrome (CdLS) is a well-described multisystem developmental disorder characterized by dysmorphic facial features, growth and behavioral deficits, and cardiac, gastrointestinal, and limb anomalies. The limb defects seen in CdLS can be mild, with small feet or hands only, or can be severe, with variable deficiency defects involving primarily the ulnar structures and ranging from mild hypoplasia of the fifth digit to complete absence of the forearm. Interestingly, the upper limbs are typically much more involved than the lower extremities that generally manifest with small feet and 2-3 syndactyly of the toes and shortened fourth metatarsal. The upper limbs often manifest asymmetric involvement. The limb findings in our cohort of 378 individuals with CdLS demonstrate a consistent pattern of laterality and symmetry involvement (with increased severity of right-sided limb in individuals with asymmetric limb defects) and a correlation of more significant limb defects with an increased risk of other structural anomalies, and more severe behavioral outcomes. Additionally, we found that individuals with mutations in NIPBL were most likely to have limb defects compared to mutations in other genes with nonsense, exonic deletion, and frameshift mutations being most prevalent in those with limb defects. Characterization of the limb differences in children with CdLS may provide a tool to assist in genetic counseling and determining prognosis. This paper will review the limb involvement in a large cohort of individuals with CdLS assessing the correlation with molecular etiologies, symmetry, additional structural birth defects, and cognitive outcomes. © 2016 Wiley Periodicals, Inc.
Assuntos
Síndrome de Cornélia de Lange/genética , Deformidades Congênitas dos Membros/genética , Criança , Transtornos Cognitivos , Anormalidades Congênitas , Síndrome de Cornélia de Lange/patologia , Humanos , Deformidades Congênitas das Extremidades Inferiores/genética , Mutação , Estudos Retrospectivos , Deformidades Congênitas das Extremidades Superiores/genéticaRESUMO
Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for â¼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
Assuntos
Fontanelas Cranianas/anormalidades , Síndrome de Cornélia de Lange/enzimologia , Anormalidades do Olho/enzimologia , Genes Ligados ao Cromossomo X , Histona Desacetilases/genética , Hipertelorismo/enzimologia , Proteínas Repressoras/genética , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Fontanelas Cranianas/enzimologia , Síndrome de Cornélia de Lange/genética , Anormalidades do Olho/genética , Feminino , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Hipertelorismo/genética , Lactente , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Fenótipo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Alinhamento de SequênciaRESUMO
BACKGROUND: Conditions associated with sudden cardiac arrest/death (SCA/D) in youth often have a genetic etiology. While SCA/D is uncommon, a pro-active family screening approach may identify these inherited structural and electrical abnormalities prior to symptomatic events and allow appropriate surveillance and treatment. This study investigated the diagnostic utility of exome sequencing (ES) by evaluating the capture and coverage of genes related to SCA/D. METHODS: Samples from 102 individuals (13 with known molecular etiologies for SCA/D, 30 individuals without known molecular etiologies for SCA/D and 59 with other conditions) were analyzed following exome capture and sequencing at an average read depth of 100X. Reads were mapped to human genome GRCh37 using Novoalign, and post-processing and analysis was done using Picard and GATK. A total of 103 genes (2,190 exons) related to SCA/D were used as a primary filter. An additional 100 random variants within the targeted genes associated with SCA/D were also selected and evaluated for depth of sequencing and coverage. Although the primary objective was to evaluate the adequacy of depth of sequencing and coverage of targeted SCA/D genes and not for primary diagnosis, all patients who had SCA/D (known or unknown molecular etiologies) were evaluated with the project's variant analysis pipeline to determine if the molecular etiologies could be successfully identified. RESULTS: The majority of exons (97.6 %) were captured and fully covered on average at minimum of 20x sequencing depth. The proportion of unique genomic positions reported within poorly covered exons remained small (4 %). Exonic regions with less coverage reflect the need to enrich these areas to improve coverage. Despite limitations in coverage, we identified 100 % of cases with a prior known molecular etiology for SCA/D, and analysis of an additional 30 individuals with SCA/D but no known molecular etiology revealed a diagnostic answer in 5/30 (17 %). We also demonstrated 95 % of 100 randomly selected reported variants within our targeted genes would have been picked up on ES based on our coverage analysis. CONCLUSIONS: ES is a helpful clinical diagnostic tool for SCA/D given its potential to successfully identify a molecular diagnosis, but clinicians should be aware of limitations of available platforms from technical and diagnostic perspectives.
Assuntos
Morte Súbita Cardíaca , Exoma/genética , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adolescente , Alelos , Criança , Genoma Humano , Humanos , Análise de Sequência de DNA , Adulto JovemRESUMO
Hearing loss is a relatively common condition in children, occurring in approximately 2 out of every 1,000 births with approximately 50% of reported diagnoses having a primary genetic etiology. Given the prevalence and genetic component of hearing loss, coupled with a trend toward early diagnosis with the institution of universal newborn hearing screening, The Genetics of Hearing Loss Clinic was established at The Children's Hospital of Philadelphia to manage the diagnosis, testing, and genetic counseling for individuals and families. This paper described a cohort of 660 individuals with a diagnosis of hearing loss evaluated between July 2008 and July 2015 in the Genetics of Hearing Loss Clinic. To elucidate the cause of hearing loss in this cohort for better management and prognostication, testing included single nucleotide polymorphism chromosomal microarray, hearing loss next generation sequencing panel, and additional clinical tests inclusive of thyroid and renal function studies, temporal bone magnetic resonance imaging, and electrocardiogram. Of those evaluated, most had bilateral sensorineural hearing loss, occurring in 489/660 (74%). Additionally, 612/660 (93%) of patients presented with a nonsyndromic form of hearing loss (no other observed clinical findings at the time of exam), of which pathogenic mutations in GJB2 were most prevalent. Of the individuals with syndromic manifestations (48/660), Usher and Waardenburg syndrome were most commonly observed. A family history of hearing loss (first degree relative) was present in 12.6% of families with available information. Through molecular analyses, clinical examination, and laboratory testing, a definitive etiologic diagnosis was established in 157/660 (23.8%) of individuals. © 2016 Wiley Periodicals, Inc.
Assuntos
Perda Auditiva/diagnóstico , Perda Auditiva/epidemiologia , Adolescente , Criança , Pré-Escolar , Conexinas/genética , Gerenciamento Clínico , Eletrocardiografia , Feminino , Aconselhamento Genético , Testes Genéticos , Genótipo , Perda Auditiva/genética , Humanos , Lactente , Recém-Nascido , Rim/anormalidades , Imageamento por Ressonância Magnética , Masculino , Mutação , Avaliação de Resultados em Cuidados de Saúde , Vigilância da População , Prevalência , Síndrome , Osso Temporal/diagnóstico por imagem , Osso Temporal/patologia , Glândula Tireoide/anormalidadesRESUMO
Pallister-Killian syndrome (PKS) is a multi-system developmental disorder caused by tetrasomy 12p that exhibits tissue-limited mosaicism. Probands with PKS often demonstrate a unique growth profile consisting of macrosomia at birth with deceleration of growth postnatally. We have previously demonstrated that cultured skin fibroblasts from PKS probands have significantly elevated expression of insulin-like growth factor binding protein-2 (IGFBP2). To further evaluate the role of IGFBP2 in PKS, the amount of IGFBP2 secreted from cultured skin fibroblast cell lines and serum IGFBP2 levels were measured in probands with PKS. Approximately 60% of PKS fibroblast cell lines secreted higher levels of IGFBP2 compared to control fibroblasts, although the remaining 40% of PKS samples produced comparable level of IGFBP2 to that of control fibroblasts. Serum IGFBP2 levels were also measured in PKS probands and were elevated in 40% of PKS probands. PKS probands with elevated IGFBP2 manifested with severe postnatal growth retardation. IGFBPs are the family of related proteins that bind IGFs with high affinity and are typically thought to attenuate IGF action. We suggest that elevated IGFBP2 levels might play a role in the growth retardation phenotype of PKS.
Assuntos
Transtornos Cromossômicos/genética , Deficiências do Desenvolvimento/genética , Fibroblastos/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Mosaicismo , Estudos de Casos e Controles , Linhagem Celular , Criança , Pré-Escolar , Transtornos Cromossômicos/sangue , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 12/genética , Metilação de DNA , Deficiências do Desenvolvimento/sangue , Deficiências do Desenvolvimento/patologia , Feminino , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Lactente , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Cariotipagem , Masculino , Fenótipo , Regiões Promotoras GenéticasRESUMO
Cornelia de Lange Syndrome (CdLS) is the most common example of disorders of the cohesin complex, or cohesinopathies. There are a myriad of clinical issues facing individuals with CdLS, particularly in the neurodevelopmental system, which also have implications for the parents and caretakers, involved professionals, therapists, and schools. Basic research in developmental and cell biology on cohesin is showing significant progress, with improved understanding of the mechanisms and the possibility of potential therapeutics. The following abstracts are presentations from the 6th Cornelia de Lange Syndrome Scientific and Educational Symposium, which took place on June 25-26, 2014, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting in Costa Mesa, CA. The Research Committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board. In addition to the scientific and clinical discussions, there were educationally focused talks related to practical aspects of behavior and development. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/genética , Regulação da Expressão Gênica no Desenvolvimento , Mutação , Adulto , Animais , California , Proteínas de Ciclo Celular/metabolismo , Criança , Proteínas Cromossômicas não Histona/metabolismo , Síndrome de Cornélia de Lange/metabolismo , Síndrome de Cornélia de Lange/patologia , Modelos Animais de Doenças , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Humanos , Camundongos , Fenótipo , Transdução de Sinais , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , CoesinasAssuntos
Fissura Palatina/genética , Deficiências do Desenvolvimento/genética , Doenças em Gêmeos/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fatores de Transcrição/genética , Criança , Fissura Palatina/complicações , Fissura Palatina/fisiopatologia , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/fisiopatologia , Doenças em Gêmeos/fisiopatologia , Humanos , Masculino , Mutação Puntual , Gêmeos Monozigóticos/genéticaRESUMO
OBJECTIVE: To investigate the prevalence and relative risk of semicircular canal dehiscence (SCD) in pediatric patients with CDH23 pathogenic variants (Usher syndrome or non-syndromic deafness) compared with age-matched controls. STUDY DESIGN: Retrospective cohort study. SETTING: Multi-institutional study. PATIENTS: Pediatric patients (ages 0-5 years) were compared based on the presence of biallelic pathogenic variants in CDH23 with pediatric controls who underwent computed tomography (CT) temporal bone scan for alternative purposes. INTERVENTIONS: Retrospective review of diagnostic high resolution CT temporal bone scans and magnetic resonance imaging (MRI) for evaluation of SCD. MAIN OUTCOME MEASURES: Superior and posterior semicircular canals were evaluated by a neuroradiologist for presence of SCD or abnormal development. RESULTS: Forty-two CT scans were reviewed for SCD. Eighty-six percent of the CDH23 variant group had abnormalities in at least one canal compared with only 12% in age-matched controls. In the CDH23 variant group there were four patients with superior SCD (57%, RRâ=â10.0) and three patients with posterior canal abnormalities (43%, RRâ=â7.5) compared with two, and two patients, respectively, in the control population. Four CDH23 variant children had bilateral abnormalities. One child had thinning or dehiscence in both the superior and posterior canals. Relative risk of SCD in children with CDH23 pathogenic variants is 7.5 (pâ<â0.001) compared with the pediatric control population. CONCLUSIONS: Children with a CDH23 pathogenic variants are at significantly increased risk of having SCD and this may be a contributing factor to the vestibular dysfunction in Usher syndrome type 1D patient population.
Assuntos
Caderinas/genética , Otopatias/genética , Canais Semicirculares/patologia , Alelos , Proteínas Relacionadas a Caderinas , Pré-Escolar , Otopatias/diagnóstico por imagem , Otopatias/epidemiologia , Otopatias/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Prevalência , Estudos Retrospectivos , Fatores de Risco , Canais Semicirculares/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.