RESUMO
Chromosomal microarray analysis (CMA) is typically performed for investigation of autism using blood DNA. However, blood collection poses significant challenges for autistic children with repetitive behaviors and sensory and communication issues, often necessitating physical restraint or sedation. Noninvasive saliva collection offers an alternative, however, no published studies to date have evaluated saliva DNA for CMA in autism. Furthermore, previous reports suggest that saliva is suboptimal for detecting copy number variation. We therefore aimed to evaluate saliva DNA for single nucleotide polymorphism (SNP) CMA in autistic children. Saliva DNA from 48 probands and parents (n = 133) was obtained with a mean concentration of 141.7 ng/µL. SNP CMA was successful in 131/133 (98.5%) patients from which we correlated the size and accuracy of a copy number variant(s) called between a proband and carrier parent, and for a subgroup (n = 17 probands) who had a previous CMA using blood sample. There were no discordant copy number variant results between the proband and carrier parent, or the subgroup, however, there was an acceptable mean size difference of 0.009 and 0.07 Mb, respectively. Our findings demonstrate that saliva DNA can be an alternative for SNP CMA in autism, which avoids blood collection with significant implications for clinical practice guidelines.
Assuntos
Transtorno Autístico , Criança , Humanos , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Variações do Número de Cópias de DNA/genética , Saliva , Polimorfismo de Nucleotídeo Único , Análise em Microsséries , DNARESUMO
Congenital cataracts are one of the major causes of childhood-onset blindness around the world. Genetic diagnosis provides benefits through avoidance of unnecessary tests, surveillance of extraocular features, and genetic family information. In this study, we demonstrate the value of genome sequencing in improving diagnostic yield in congenital cataract patients and families. We applied genome sequencing to investigate 20 probands with congenital cataracts. We examined the added value of genome sequencing across a total cohort of 52 probands, including 14 unable to be diagnosed using previous microarray and exome or panel-based approaches. Although exome or genome sequencing would have detected the variants in 35/52 (67%) of the cases, specific advantages of genome sequencing led to additional diagnoses in 10% (5/52) of the overall cohort, and we achieved an overall diagnostic rate of 77% (40/52). Specific benefits of genome sequencing were due to detection of small copy number variants (2), indels in repetitive regions (2) or single-nucleotide variants (SNVs) in GC-rich regions (1), not detectable on the previous microarray, exome sequencing, or panel-based approaches. In other cases, SNVs were identified in cataract disease genes, including those newly identified since our previous study. This study highlights the additional yield of genome sequencing in congenital cataracts.
Assuntos
Catarata , Exoma , Catarata/diagnóstico , Catarata/genética , Mapeamento Cromossômico , Variações do Número de Cópias de DNA/genética , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Sequenciamento do ExomaRESUMO
Despite the increasing diagnostic rate of genomic sequencing, the genetic basis of more than 50% of heritable kidney disease remains unresolved. Kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of individuals affected by inherited renal disease represent a potential, but unvalidated, platform for the functional validation of novel gene variants and investigation of underlying pathogenetic mechanisms. In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies. IFT140 plays a key role in retrograde intraflagellar transport, but the precise downstream cellular mechanisms responsible for disease presentation remain unknown. A one-step reprogramming and gene-editing protocol was used to derive both uncorrected proband iPSCs and isogenic gene-corrected iPSCs, which were differentiated to kidney organoids. Proband organoid tubules demonstrated shortened, club-shaped primary cilia, whereas gene correction rescued this phenotype. Differential expression analysis of epithelial cells isolated from organoids suggested downregulation of genes associated with apicobasal polarity, cell-cell junctions, and dynein motor assembly in proband epithelial cells. Matrigel cyst cultures confirmed a polarization defect in proband versus gene-corrected renal epithelium. As such, this study represents a "proof of concept" for using proband-derived iPSCs to model renal disease and illustrates dysfunctional cellular pathways beyond the primary cilium in the setting of IFT140 mutations, which are established for other NPHP genotypes.
Assuntos
Cílios/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Rim/patologia , Organoides/patologia , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Transporte/química , Proteínas de Transporte/genética , Células Cultivadas , Reprogramação Celular/genética , Ataxia Cerebelar/genética , Células Epiteliais/metabolismo , Feminino , Fibroblastos/patologia , Flagelos/metabolismo , Edição de Genes , Perfilação da Expressão Gênica , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Rim/diagnóstico por imagem , Fenótipo , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Retinose Pigmentar/genética , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Sequenciamento do ExomaRESUMO
PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.
Assuntos
Anormalidades do Olho , Oftalmopatias Hereditárias , Proteínas ADAMTS , Segmento Anterior do Olho , Citocromo P-450 CYP1B1/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Fatores de Transcrição Forkhead/genética , Humanos , Mutação , LinhagemRESUMO
There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults. We identified 2 families with presumed adult-diagnosed nonsyndromic NPHP and negative diagnostic genetic testing results from our Renal Genetics Clinic. Both had 2 affected siblings without extrarenal phenotypes. After informed consent, research whole-genome sequencing was undertaken. Biallelic NPHP4 variants were identified in trans and clinically confirmed in all 4 affected individuals, confirming a genetic diagnosis. Participant 1 of the first family (F1P1) had kidney failure diagnosed at 19 years of age. An affected younger sibling (F1P2) reached kidney failure at age 15 years after kidney biopsy suggested NPHP. Pathogenic variants detected in NPHP4 in this family were NM_015102.4:c.3766C>T (p.Gln1256*) and a 31-kb deletion affecting exons 12 to 16. In the second family, F2P3 reached kidney failure at age 27 years having undergone kidney biopsy suggesting NPHP. An affected younger sibling (F2P4) has chronic kidney disease stage 4 at age 39 years. The NPHP4 variants detected were NM_015102.4:c.1998_1999del (p.Tyr667Phefs*23) and c.3646G>T (p.Asp1216Tyr). The latter variant was initially missed in diagnostic sequencing due to inadequate NPHP4 coverage (94.3% exonic coverage). With these reports, we identify NPHP4 as an appreciable genetic cause for adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.
Assuntos
Doenças Renais Císticas/genética , Rim/patologia , Proteínas/genética , Insuficiência Renal Crônica/genética , Adolescente , Adulto , Austrália , Códon sem Sentido , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Falência Renal Crônica/genética , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Adulto JovemRESUMO
Inherited kidney disease encompasses a broad range of disorders, with both multiple genes contributing to specific phenotypes and single gene defects having multiple clinical presentations. Advances in sequencing capacity may allow a genetic diagnosis for familial renal disease, by testing the increasing number of known causative genes. However, there has been limited translation of research findings of causative genes into clinical settings. Here, we report the results of a national accredited diagnostic genetic service for familial renal disease. An expert multidisciplinary team developed a targeted exomic sequencing approach with ten curated multigene panels (207 genes) and variant assessment individualized to the patient's phenotype. A genetic diagnosis (pathogenic genetic variant[s]) was identified in 58 of 135 families referred in two years. The genetic diagnosis rate was similar between families with a pediatric versus adult proband (46% vs 40%), although significant differences were found in certain panels such as atypical hemolytic uremic syndrome (88% vs 17%). High diagnostic rates were found for Alport syndrome (22 of 27) and tubular disorders (8 of 10), whereas the monogenic diagnostic rate for congenital anomalies of the kidney and urinary tract was one of 13. Quality reporting was aided by a strong clinical renal and genetic multidisciplinary committee review. Importantly, for a diagnostic service, few variants of uncertain significance were found with this targeted, phenotype-based approach. Thus, use of targeted massively parallel sequencing approaches in inherited kidney disease has a significant capacity to diagnose the underlying genetic disorder across most renal phenotypes.
Assuntos
Exoma/genética , Testes Genéticos/métodos , Nefropatias/diagnóstico , Adolescente , Adulto , Idoso , Austrália , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Aconselhamento Genético/métodos , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Recém-Nascido , Nefropatias/genética , Nefropatias/terapia , Masculino , Pessoa de Meia-Idade , Fenótipo , Medicina de Precisão/métodos , Análise de Sequência de DNA , Adulto JovemRESUMO
Congenital cataracts are a significant cause of lifelong visual loss. They may be isolated or associated with microcornea, microphthalmia, anterior segment dysgenesis (ASD) and glaucoma, and there can be syndromic associations. Genetic diagnosis is challenging due to marked genetic heterogeneity. In this study, next-generation sequencing (NGS) of 32 cataract-associated genes was undertaken in 46 apparently nonsyndromic congenital cataract probands, around half sporadic and half familial cases. We identified pathogenic variants in 70% of cases, and over 68% of these were novel. In almost two-thirds (20/33) of these cases, this resulted in new information about the diagnosis and/or inheritance pattern. This included identification of: new syndromic diagnoses due to NHS or BCOR mutations; complex ocular phenotypes due to PAX6 mutations; de novo autosomal-dominant or X-linked mutations in sporadic cases; and mutations in two separate cataract genes in one family. Variants were found in the crystallin and gap junction genes, including the first report of severe microphthalmia and sclerocornea associated with a novel GJA8 mutation. Mutations were also found in rarely reported genes including MAF, VIM, MIP, and BFSP1. Targeted NGS in presumed nonsyndromic congenital cataract patients provided significant diagnostic information in both familial and sporadic cases.
Assuntos
Catarata/diagnóstico , Catarata/genética , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Alelos , Sequência de Aminoácidos , Criança , Pré-Escolar , Biologia Computacional/métodos , Conexinas/genética , Cristalinas/genética , Análise Mutacional de DNA , Exoma , Feminino , Genes Ligados ao Cromossomo X , Humanos , Padrões de Herança , Masculino , Proteínas de Membrana , Proteínas Nucleares/genética , Fator de Transcrição PAX6/genética , Linhagem , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-maf/genética , Proteínas Repressoras/genéticaRESUMO
Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-ß signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-ß-signaling pathway.
Assuntos
Aracnodactilia/genética , Craniossinostoses/genética , Proteínas de Ligação a DNA/genética , Éxons , Genes Dominantes , Síndrome de Marfan/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Proteínas de Ligação a DNA/química , Fácies , Feminino , Ordem dos Genes , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Fenótipo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/química , Alinhamento de Sequência , Adulto JovemRESUMO
BACKGROUND: Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned adults with obesity 1:1 (stratified by sex and obesity class) to receive intranasal oxytocin (24 IU) or placebo four times daily for 8 weeks. The primary end point was change in body weight (kg) from baseline to week 8. Key secondary end points included change in body composition (total fat mass [g], abdominal visceral adipose tissue [cm2], and liver fat fraction [proportion; range, 0 to 1; higher values indicate a higher proportion of fat]), and resting energy expenditure (kcal/day; adjusted for lean mass) from baseline to week 8 and caloric intake (kcal) at an experimental test meal from baseline to week 6. RESULTS: Sixty-one participants (54% women; mean age ± standard deviation, 33.6 ± 6.2 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 36.9 ± 4.9) were randomly assigned. There was no difference in body weight change from baseline to week 8 between oxytocin and placebo groups (0.20 vs. 0.26 kg; P=0.934). Oxytocin (vs. placebo) was not associated with beneficial effects on body composition or resting energy expenditure from baseline to week 8 (total fat: difference [95% confidence interval], 196.0 g [-1036 to 1428]; visceral fat: 3.1 cm2 [-11.0 to 17.2]; liver fat: -0.01 [-0.03 to 0.01]; resting energy expenditure: -64.0 kcal/day [-129.3 to 1.4]). Oxytocin compared with placebo was associated with reduced caloric intake at the test meal (-31.4 vs. 120.6 kcal; difference [95% confidence interval], -152.0 kcal [-302.3 to -1.7]). There were no serious adverse events. Incidence and severity of adverse events did not differ between groups. CONCLUSIONS: In this randomized, placebo-controlled trial in adults with obesity, intranasal oxytocin administered four times daily for 8 weeks did not reduce body weight. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT03043053.).
Assuntos
Administração Intranasal , Obesidade , Ocitocina , Humanos , Ocitocina/administração & dosagem , Ocitocina/farmacologia , Ocitocina/efeitos adversos , Feminino , Masculino , Adulto , Obesidade/tratamento farmacológico , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Erectile dysfunction medications are being prescribed frequently; however, little is known about the amount of sexual health screening occurring in this setting. METHODS: A retrospective cohort study evaluating sexual health and sexually transmitted infection screening occurring in veterans receiving initial erectile dysfunction medication prescription was conducted. RESULTS: A total of 252 patients received initial erectile dysfunction medication prescriptions between October 1, 2009, and December 31, 2009; had at least 1 health care provider visit 12 months before the date of initial prescription; and had no documentation of previous erectile dysfunction medication use. Approximately 3% of these patients had any aspect of a sexual history recorded in the 24 months surrounding initial erectile dysfunction medication prescription. Sexually transmitted infection screening was 9.9% for syphilis, 4.8% for HIV, and 4.3% for gonorrhea/chlamydia before prescription, with only a slight increase in HIV screening after prescription. CONCLUSIONS: Minimal sexual health assessment is being performed during the time surrounding initial prescription of erectile dysfunction medication. Further work needs to evaluate patient and provider barriers to basic elements of sexual health care, such as taking sexual histories or screening for sexually transmitted infections.
Assuntos
Disfunção Erétil/tratamento farmacológico , Comportamento Sexual/estatística & dados numéricos , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/epidemiologia , Veteranos , Adulto , Idoso , Idoso de 80 Anos ou mais , Aconselhamento Diretivo , Registros Eletrônicos de Saúde , Disfunção Erétil/diagnóstico , Disfunção Erétil/epidemiologia , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Serologic tests for syphilis results at the time of diagnosis are the basis for evaluating response to syphilis therapy. After treatment, however, serologic tests for syphilis titers may continue to increase for several weeks. We evaluated rapid plasma reagin (RPR) titer variation during the 14 days after therapy using data from a recent large, prospective randomized controlled trial. METHODS: Prospectively enrolled participants in North America and Madagascar with primary, secondary, or early latent syphilis were randomly assigned to penicillin, doxycycline (in the case of penicillin allergy), or azithromycin treatment. Blood for RPR analysis was drawn at days 0, 7, and 14 posttreatment. All RPR titers were determined simultaneously at a central laboratory. RESULTS: Four hundred and seventy patients had data available for at least 2 of 3 RPR measurements. Overall, 20% of patients showed a titer increase of at least 1 dilution in the 14 days after therapy. The greatest proportion of titer increases following therapy was observed in patients with primary syphilis. Comparing outcome of therapy using the initial (day 0) RPR titer versus the maximal RPR titer (during 14 days) resulted in outcome reclassification in 2.98% of participants. CONCLUSIONS: Despite the fact that about 20% of early syphilis patients had increases in RPR titers immediately after treatment, these changes rarely influenced assessment of therapeutic outcome. Only 3% of patients treated would have been reclassified.
Assuntos
Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Doxiciclina/administração & dosagem , Penicilinas/administração & dosagem , Reaginas/sangue , Sorodiagnóstico da Sífilis/métodos , Sífilis/sangue , Sífilis/tratamento farmacológico , Treponema pallidum/isolamento & purificação , Adulto , Análise de Variância , Anticorpos Antibacterianos/sangue , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Fatores Imunológicos/sangue , Madagáscar/epidemiologia , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Treponema pallidum/imunologia , Adulto JovemRESUMO
BACKGROUND: Social and communication impairments are core deficits and prognostic indicators of autism. We evaluated the impact of supplementing a comprehensive intervention with a curriculum targeting socially synchronous behavior on social outcomes of toddlers with autism spectrum disorders (ASD). METHODS: Fifty toddlers with ASD, ages 21 to 33 months, were randomized to one of two six-month interventions: Interpersonal Synchrony or Non-Interpersonal Synchrony. The interventions provided identical intensity (10 hours per week in classroom), student-to-teacher ratio, schedule, home-based parent training (1.5 hours per month), parent education (38 hours), and instructional strategies, except the Interpersonal Synchrony condition provided a supplementary curriculum targeting socially engaged imitation, joint attention, and affect sharing; measures of these were primary outcomes. Assessments were conducted pre-intervention, immediately post-intervention, and, to assess maintenance, at six-month follow-up. Random effects models were used to examine differences between groups over time. Secondary analyses examined gains in expressive language and nonverbal cognition, and time effects during the intervention and follow-up periods. RESULTS: A significant treatment effect was found for socially engaged imitation (p = .02), with more than doubling (17% to 42%) of imitated acts paired with eye contact in the Interpersonal Synchrony group after the intervention. This skill was generalized to unfamiliar contexts and maintained through follow-up. Similar gains were observed for initiation of joint attention and shared positive affect, but between-group differences did not reach statistical significance. A significant time effect was found for all outcomes (p < .001); greatest change occurred during the intervention period, particularly in the Interpersonal Synchrony group. CONCLUSIONS: This is the first ASD randomized trial involving toddlers to identify an active ingredient for enhancing socially engaged imitation. Adding social engagement targets to intervention improves short-term outcome at no additional cost to the intervention. The social, language, and cognitive gains in our participants provide evidence for plasticity of these developmental systems in toddlers with ASD. http://www.clinicaltrials.gov/ct2/show/NCT00106210?term = landa&rank = 3.
Assuntos
Terapia Comportamental/métodos , Transtornos Globais do Desenvolvimento Infantil/psicologia , Transtornos Globais do Desenvolvimento Infantil/terapia , Cognição , Comunicação , Comportamento Imitativo , Pais/educação , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Testes Neuropsicológicos , Resultado do Tratamento , Comportamento VerbalRESUMO
Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.
RESUMO
New technologies such as genomics present opportunities to deliver precision medicine, including in the diagnosis of rare kidney disorders. Simultaneously, social media platforms such as Twitter can provide rapid and wide-reaching information dissemination in health care and science. We present 2 cases in which the reporting of a novel genetic cause for human kidney disease was communicated through Twitter and then subsequently noted by treating clinicians, thereby resulting in rapid clinical diagnostic translation. In 1 family, this involved the reporting of heterozygous variants in GREB1L relating to autosomal dominant unilateral or bilateral renal agenesis, and in the other family, this involved biallelic variants in CLDN10 relating to autosomal recessive hypokalemic renal tubular phenotypes. The times from Twitter notification to clinical diagnostic genetic report for these families were 111 and 200 days, respectively. Although caution is required, these cases show that social media platforms can contribute to rapid and accessible academic communication that may benefit clinicians, genomics-based researchers, and patients and families affected by rare kidney diseases.
RESUMO
CONTEXT: To our knowledge, no prospective studies of the developmental course of early and later diagnosis of autism spectrum disorders from 14 months of age exist. OBJECTIVE: To examine patterns of development from 14 to 24 months in children with early and later diagnosis of autism spectrum disorders. DESIGN: Prospective, longitudinal design in which 125 infants at high and low risk for autism were tested from age 14 to 36 months. Comprehensive standardized assessments included measures of social, communication, and play behavior. SETTING: Testing occurred at a major medical and research institution as part of a large, ongoing longitudinal study. PARTICIPANTS: Low-risk controls (n = 18) and siblings of children with autism, grouped on the basis of outcome diagnostic classification at 30 or 36 months: autism spectrum disorders (early diagnosis, n = 16; later diagnosis, n = 14), broader autism phenotype (n = 19), and non-broader autism phenotype (n = 58). MAIN OUTCOME MEASURES: Social, communication, and symbolic abilities were assessed. RESULTS: Social, communication, and play behavior in the early-diagnosis group differed from that in all other groups by 14 months of age. By 24 months, the later-diagnosis group differed from the non-autism spectrum disorder groups in social and communication behavior, but not from the early-diagnosis group. Examination of growth trajectories suggests that autism may involve developmental arrest, slowing, or even regression. CONCLUSION: This study provides insight into different patterns of development of children with early vs later diagnosis of autism spectrum disorders.
Assuntos
Transtorno Autístico/diagnóstico , Desenvolvimento Infantil/fisiologia , Comunicação não Verbal , Socialização , Fatores Etários , Transtorno Autístico/genética , Transtorno Autístico/psicologia , Pré-Escolar , Transtornos da Comunicação/diagnóstico , Transtornos da Comunicação/genética , Transtornos da Comunicação/psicologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/psicologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Testes de Linguagem/estatística & dados numéricos , Estudos Longitudinais , Masculino , Comunicação não Verbal/fisiologia , Inventário de Personalidade/estatística & dados numéricos , Fenótipo , Jogos e Brinquedos/psicologia , Estudos Prospectivos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Fatores de Risco , Irmãos/psicologia , Comportamento Social , Estatísticas não ParamétricasRESUMO
Infections are one of the most common causes of mortality in immunocompromised patients. In patients diagnosed with hematologic malignancies, treatment with stem cell transplants (SCT) or T-cell suppressing chemotherapy increases the risk of central nervous system (CNS) infections, of which toxoplasmosis is the most common. We report the case of a 63â¯year-old woman with chronic lymphocytic leukemia (CLL) that presented with gait instability and visual changes. Intracranial lesions were noted on initial neuro-imaging. A rapid decline in the patient's mental status warranted an urgent biopsy of the lesions that revealed tachyzoites consistent with toxoplasmosis. In the presence of diffuse brain lesions that lack a metastatic pattern or contrast enhancement, a common approach is to perform biopsy only after a battery of non-invasive testing. This diagnostic delay may take several days, exposing the patient to a rapidly fatal infection. This report illustrates the utility of early brain biopsy in high-risk patients with hematologic malignancies and CNS lesions.
Assuntos
Hospedeiro Imunocomprometido , Leucemia Linfocítica Crônica de Células B/complicações , Toxoplasmose Cerebral/diagnóstico , Toxoplasmose Cerebral/imunologia , Biópsia , Feminino , Humanos , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologiaRESUMO
PURPOSE: To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy. METHOD: We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants. RESULTS: The yield of pathogenic variants was 28.5% (nâ¯=â¯30/105), highest in early onset EE <3â¯months including Ohtahara syndrome (52%, nâ¯=â¯10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6â¯m vs 1.1y, pâ¯<â¯0.001, OR 0.6/year, Pâ¯<â¯0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach ($5990 Australian dollars (AUD) vs $13069 AUD ; pâ¯=â¯0.02) among the patients with identified pathogenic variants. CONCLUSION: Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing.
Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Adolescente , Criança , Pré-Escolar , Análise Custo-Benefício , Epilepsia/economia , Feminino , Predisposição Genética para Doença , Testes Genéticos/economia , Testes Genéticos/métodos , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/economia , Humanos , Lactente , Masculino , Fenótipo , Estudos RetrospectivosRESUMO
Previous experimental studies have demonstrated the emergence of narrowband local field potential oscillations during epileptic seizures in which the underlying neural activity appears to be completely asynchronous. We derive a mathematical model explaining how this counterintuitive phenomenon may occur, showing that a population of independent, completely asynchronous neurons may produce narrowband oscillations if each neuron fires quasi-periodically, without requiring any intrinsic oscillatory cells or feedback inhibition. This quasi-periodicity can occur through cells with similar frequency-current ([Formula: see text]-[Formula: see text]) curves receiving a similar, high amount of uncorrelated synaptic noise. Thus, this source of oscillatory behavior is distinct from the usual cases (pacemaker cells entraining a network, or oscillations being an inherent property of the network structure), as it requires no oscillatory drive nor any specific network or cellular properties other than cells that repetitively fire with continual stimulus. We also deduce bounds on the degree of variability in neural spike-timing which will permit the emergence of such oscillations, both for action potential- and postsynaptic potential-dominated LFPs. These results suggest that even an uncoupled network may generate collective rhythms, implying that the breakdown of inhibition and high synaptic input often observed during epileptic seizures may generate narrowband oscillations. We propose that this mechanism may explain why so many disparate epileptic and normal brain mechanisms can produce similar high frequency oscillations.
Assuntos
Potenciais de Ação/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Periodicidade , Algoritmos , Animais , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Epilepsia/fisiopatologia , HumanosRESUMO
BACKGROUND: The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. METHODS AND RESULTS: The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2. Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. CONCLUSIONS: Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.
Assuntos
Aorta Torácica , Doenças da Aorta/genética , Heterozigoto , Mutação , Complicações Cardiovasculares na Gravidez/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/mortalidade , Doenças da Aorta/cirurgia , Austrália/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Fenótipo , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/mortalidade , Complicações Cardiovasculares na Gravidez/cirurgia , Prevalência , Modelos de Riscos Proporcionais , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos/epidemiologia , Procedimentos Cirúrgicos VascularesRESUMO
Marfan syndrome (MFS) is a disorder of the extracellular matrix caused by mutations in the gene encoding fibrillin-1 (FBN1). Recent studies have illustrated the variability in disease severity and clinical manifestations of MFS. Useful genotype-phenotype correlations have been slow to emerge. We screened 57 unrelated patients with MFS or a Marfan-like phenotype using a combination of SSCP and/or DHPLC. We detected 49 different FBN1 mutations, 30 (62%) of which were novel. The mutations comprised 38 substitutions (78%), 10 deletions (20%), and one duplication (2%). There were 28 missense (57%), nine frameshift (18%), eight splice site (16%), and four nonsense mutations (8 %). Genotype-phenotype analysis revealed that patients with an identified FBN1 mutation were more likely to have ectopia lentis and cardiovascular complications compared to those without an identifiable mutation (relative risks of 4.6 and 1.9, respectively). Ectopia lentis was also found to be more prevalent in patients whose mutations involved a cysteine substitution (relative risk 1.6) and less prevalent in those with premature termination mutations (relative risk 0.4). In our hands, we achieved 93% mutation detection for DHPLC analysis of patients who fulfilled the Ghent criteria. Further analysis of detailed clinical information and mutation data may help to anticipate the clinical consequences of specific FBN1 mutations.