RESUMEN
Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders1. Their involvement in disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2-20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD)2,3 and population control individuals4. We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN, which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1. Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD.
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Trastorno del Espectro Autista/genética , Expansión de las Repeticiones de ADN/genética , Genoma Humano/genética , Genómica , Secuencias Repetidas en Tándem/genética , Femenino , Factores de Crecimiento de Fibroblastos/genética , Predisposición Genética a la Enfermedad , Humanos , Inteligencia/genética , Proteínas de Unión a Hierro/genética , Masculino , Proteína Quinasa de Distrofia Miotónica/genética , Motivos de Nucleótidos , Polimorfismo Genético , FrataxinaRESUMEN
PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Ratones , Animales , Humanos , Metilación de ADN/genética , Trastornos del Neurodesarrollo/genética , Discapacidad Intelectual/genética , ADN , MutaciónRESUMEN
Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.
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Senescencia Celular/fisiología , Histonas/fisiología , Aneuploidia , Nucléolo Celular/metabolismo , Niño , Cromatina/metabolismo , Metilación de ADN , Femenino , Histonas/química , Humanos , Lactante , Masculino , Persona de Mediana EdadRESUMEN
Most individuals with autism spectrum disorder (ASD)-a complex, life-long developmental disorder-do not have access to the care required to address their diverse health needs. Here, we review: (1) common barriers to healthcare access (shortage/cost of services; physician awareness; stigma); (2) barriers encountered primarily during childhood (limited screening/diagnosis; unclear referral pathways), transition to adulthood (insufficient healthcare transition services; suboptimal physician awareness of healthcare needs) and adulthood (shortage of services/limited insurance; communication difficulties with physicians; limited awareness of healthcare needs of aging adults); and (3) advances in research/program development for better healthcare access. A robust understanding of barriers to accessing healthcare across the lifespan of autistic individuals is critical to ensuring the best use of healthcare resources to improve social, physical, and mental health outcomes. Stakeholders must strengthen healthcare service provision by coming together to: better understand healthcare needs of underserved populations; strengthen medical training on care of autistic individuals; increase public awareness of ASD; promote research into/uptake of tools for ASD screening, diagnosis, and treatment; understand specific healthcare needs of autistic individuals in lower resource countries; and conduct longitudinal studies to understand the lifetime health, social, and economic impacts of ASD and enable the evaluation of novel approaches to increasing healthcare access. IMPACT: Despite the growing body of evidence, our understanding of barriers to healthcare encountered by individuals with ASD remains limited, particularly beyond childhood and in lower resource countries. We describe current and emerging barriers to healthcare access encountered by individuals with ASD across the lifespan. We recommend that stakeholders develop evidence-informed policies, programs, and technologies that address barriers to healthcare access for individuals with ASD and consider broad, equitable implementation to maximize impact.
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Trastorno del Espectro Autista , Trastorno Autístico , Transición a la Atención de Adultos , Adulto , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/psicología , Trastorno del Espectro Autista/terapia , Trastorno Autístico/diagnóstico , Comunicación , Accesibilidad a los Servicios de Salud , HumanosRESUMEN
Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
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Eccema/diagnóstico , Eccema/genética , Predisposición Genética a la Enfermedad , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/genética , Histona Desacetilasas/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas Represoras/genética , Adolescente , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Eccema/patología , Exoma/genética , Facies , Femenino , Genoma Humano/genética , Genómica/métodos , Trastornos del Crecimiento/patología , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Microcefalia/patología , Fenotipo , Secuenciación del ExomaRESUMEN
Autism spectrum disorder (ASD) is a highly heterogeneous genetic disorder with strong evidence of ASD-association currently available only for a small number of genes. This makes it challenging to identify the underlying genetic cause in many cases of ASD, and there is a continuing need for further discovery efforts. We sequenced whole genomes of 119 deeply phenotyped ASD probands in order to identify likely pathogenic variants. We prioritized variants found in each subject by predicted damage, population frequency, literature evidence, and phenotype concordance. We used Sanger sequencing to determine the inheritance status of high-priority variants where possible. We report five novel de novo damaging variants as well as several likely damaging variants of unknown inheritance; these include two novel de novo variants in the well-established ASD gene SCN2A. The availability of rich phenotypic information and its concordance with the literature allowed us to increase our confidence in pathogenicity of discovered variants, especially in probands without parental DNA. Our results contribute to the documentation of potential pathogenic variants and their associated phenotypes in individuals with ASD.
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Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Variación Genética , Secuenciación Completa del Genoma , Alelos , Sustitución de Aminoácidos , Trastorno del Espectro Autista/diagnóstico , Colombia Británica , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Mutación , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.
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Anomalías Múltiples/enzimología , Anomalías Múltiples/genética , Hipotiroidismo Congénito/enzimología , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/enzimología , Anomalías Craneofaciales/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Deformidades Congénitas de la Mano/enzimología , Deformidades Congénitas de la Mano/genética , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Femenino , Histona Metiltransferasas , Humanos , Lactante , Recién Nacido , Masculino , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismoRESUMEN
BACKGROUND: The recurrent microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurodevelopmental disorders (NDD) confounded by incomplete penetrance and variable expressivity. This inter- and intra-familial clinical variability highlights the importance of personalized genetic counselling in individuals at-risk. CASE PRESENTATION: In this study, we performed whole exome sequencing (WES) to look for other genomic alterations that could explain the clinical variability in a family with a boy presenting with NDD who inherited the dup16p11.2 from his apparently healthy mother. We identified novel splicing variants of VPS13B (8q22.2) in the proband with compound heterozygous inheritance. Two VPS13B mutations abolished the canonical splice sites resulting in low RNA expression in transformed lymphoblasts of the proband. VPS13B mutation causes Cohen syndrome (CS) consistent with the proband's phenotype (intellectual disability (ID), microcephaly, facial gestalt, retinal dystrophy, joint hypermobility and neutropenia). The new diagnosis of CS has important health implication for the proband, provides the opportunity for more meaningful and accurate genetic counselling for the family; and underscores the importance of longitudinally following patients for evolving phenotypic features. CONCLUSIONS: This is the first report of a co-occurrence of pathogenic variants with familial dup16p11.2. Our finding suggests that the variable expressivity among carriers of rare putatively pathogenic CNVs such as dup16p11.2 warrants further study by WES and individualized genetic counselling of families with such CNVs.
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Cromosomas Humanos Par 16 , Trastornos del Neurodesarrollo/genética , Proteínas de Transporte Vesicular/genética , Niño , ADN/química , ADN/aislamiento & purificación , ADN/metabolismo , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Dedos/anomalías , Duplicación de Gen , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Miopía/diagnóstico , Miopía/genética , Trastornos del Neurodesarrollo/diagnóstico , Obesidad/diagnóstico , Obesidad/genética , Linaje , Fenotipo , Empalme del ARN , Degeneración Retiniana , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genéticaRESUMEN
Autism spectrum disorder (ASD) comprises a group of complex neurodevelopmental features seen in many different forms due to variable causes. Highly impactful ASD-susceptibility genes are involved in pathways associated with brain development, chromatin remodeling, and transcription regulation. In this study, we investigate a proband with complex ASD. Whole genome sequencing revealed a novel de novo missense mutation of a highly conserved amino acid residue (NP_001289981.1:p.His516Gln; chr2:1917275; hg38) in the MYT1L neural transcription factor gene. In combination with in silico analysis on gene effect and pathogenicity, we described the proband's phenotype and made comparisons with previously reported cases to explore the spectrum of clinical features in MYT1L single nucleotide variant (SNV) cases. The phenotype-genotype correlation showed a high degree of clinical similarity with previously reported cases of missense variants in MYT1L, indicating MYT1L as the causal gene for the observed phenotype in our proband. The variant was also predicted to be damaging according to multiple in silico pathogenicity predicting tools. This study expands the clinical description of SNVs on the MYT1L gene and provides insight into its contribution to ASD.
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Trastorno del Espectro Autista , Humanos , Trastorno del Espectro Autista/genética , Fenotipo , Mutación Missense , Estudios de Asociación Genética , Regulación de la Expresión Génica , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: This study explores the validity of Paget's disease of bone (PDB) reported in unpublished skeletal reports, based on macroscopic analysis alone. MATERIALS: The high prevalence of 'suspected' Paget's disease (10.7%) in an early modern sample from St John's the Evangelist Church in Redhill, Surrey is reassessed. METHODS: Signs of PDB were examined in 53 well-preserved adults aged 35 + years using macroscopic, radiographic and histological techniques. RESULTS: Macroscopic features of PDB were identified in 8 individuals (15%), with 5 individuals later rejected using radiography. Two individuals showed classic radiographic features of PDB, with a third presenting possible features in radiography (5.7%). These three cases were confirmed by histological analysis. CONCLUSIONS: PDB should not be suggested as a single diagnosis in cases of bone hypertrophy without confirmation using radiography. SIGNIFICANCE: The growing popularity of 'big data' projects and limited collections access means that unpublished cases of PDB are often included in large scale analyses, impacting our understanding of the evolution of this disease. Using macroscopic analysis alone leads to overdiagnosis. Histological analysis is unnecessary when radiographic features are present, but provides a useful diagnostic step in long bones in advanced cases of PBD. LIMITATIONS: The radiographic sample in this study was limited to three individuals. SUGGESTIONS FOR FURTHER RESEARCH: The conclusion that radiography alone can be used to identify PDB in archaeological cases merits further research on a larger number of cases.
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Osteítis Deformante , Adulto , Huesos/patología , Humanos , Osteítis Deformante/diagnóstico por imagen , Osteítis Deformante/patología , Sobrediagnóstico , Prevalencia , RadiografíaRESUMEN
Autism spectrum disorder (ASD) describes a complex and heterogenous group of neurodevelopmental disorders. Whole genome sequencing continues to shed light on the multifactorial etiology of ASD. Dysregulated transcriptional pathways have been implicated in neurodevelopmental disorders. Emerging evidence suggests that de novo POLR2A variants cause a newly described phenotype called 'Neurodevelopmental Disorder with Hypotonia and Variable Intellectual and Behavioral Abnormalities' (NEDHIB). The variable phenotype manifests with a spectrum of features; primarily early onset hypotonia and delay in developmental milestones. In this study, we investigate a patient with complex ASD involving epilepsy and strabismus. Whole genome sequencing of the proband−parent trio uncovered a novel de novo POLR2A variant (c.1367T>C, p. Val456Ala) in the proband. The variant appears deleterious according to in silico tools. We describe the phenotype in our patient, who is now 31 years old, draw connections between the previously reported phenotypes and further delineate this emerging neurodevelopmental phenotype. This study sheds new insights into this neurodevelopmental disorder, and more broadly, the genetic etiology of ASD.
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Trastorno del Espectro Autista , Epilepsia , Discapacidad Intelectual , Conducta Autodestructiva , Estrabismo , Trastorno del Espectro Autista/genética , ARN Polimerasas Dirigidas por ADN/genética , Epilepsia/genética , Humanos , Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Estrabismo/genéticaRESUMEN
Autism severity is associated with child and maternal MAOA genotypes. We replicated and extended a previously reported association between autism severity and a functional polymorphism in the monoamine oxidase A (MAOA) promoter region, MAOA-uVNTR, in a sample of 119 males, aged 2-13 years, with autism spectrum disorder from simplex families. We demonstrated that (i) boys with the low activity 3-repeat MAOA allele had more severe sensory behaviors, arousal regulation problems, and aggression, and worse social communication skills than males with the high activity allele; and (ii) problems with aggression, as well as with fears and rituals, were modified by the mothers' genotype. Boys with the 4-repeat high activity allele who had homozygous 4-repeat mothers showed increased severity of these behaviors relative to those born to heterozygous mothers. These findings indicate the importance of considering maternal genotype in examining associations of MAOA and other genes with behavior in male offspring.
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Trastorno Autístico/psicología , Monoaminooxidasa/genética , Polimorfismo Genético , Adolescente , Análisis de Varianza , Trastorno Autístico/enzimología , Trastorno Autístico/genética , Niño , Trastornos de la Conducta Infantil/enzimología , Trastornos de la Conducta Infantil/genética , Trastornos de la Conducta Infantil/psicología , Preescolar , Genotipo , Humanos , Masculino , Repeticiones de Minisatélite/genética , Regiones Promotoras Genéticas/genéticaRESUMEN
INTRODUCTION: Percutaneous coronary intervention (PCI) activity has increased more than 6 fold in the last 15 years. Increased demand has been met by PCI centres without on-site surgical facilities. To improve communication between cardiologists and surgeons at a remote centre, we have developed a video conferencing system using standard internet links. The effect of this video data link (VDL) on referral pattern and patient selection for revascularisation was assessed prospectively after introduction of a joint cardiology conference (JCC) using the system. METHODS: Between 1st October 2005 and 31st March 2007, 1346 patients underwent diagnostic coronary angiography (CA). Of these, 114 patients were discussed at a cardiology conference (CC) attended by three consultant cardiologists (pre-VDL). In April 2007, the VDL system was introduced. Between 1st April 2007 and 30th September 2008, 1428 patients underwent diagnostic CA. Of these, 120 patients were discussed at a JCC attended by four consultant cardiologists and two consultant cardiothoracic surgeons (post-VDL). Following case-matching for patient demographics and coronary artery disease (CAD) severity and distribution, we assessed the effect upon management decisions arising from both the pre- and post-VDL JCC meetings. RESULTS: When comparing decision-making outcomes of post-VDL JCC with pre-VDL CC, significantly fewer patients were recommended for PCI (36.8% vs. 17.2% respectively, p = 0.001) and significantly more patients were recommended for surgery (21.1% vs. 48.4% respectively, p < 0.001). There were no significant differences in waiting times for PCI following JCC discussion; however, waiting times for surgical revascularisation were significantly reduced (140.9 ± 71.8 days vs. 99.4 ± 56.6 days respectively, p = 0.045). CONCLUSIONS: The VDL system provides a highly practical method for PCI centres without onsite surgical cover to discuss complex patients requiring coronary revascularisation and significantly increases the number of patients referred for surgical revascularisation rather than PCI.
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Angiografía Coronaria/métodos , Enfermedad Coronaria/terapia , Revascularización Miocárdica/métodos , Comunicación por Videoconferencia , Anciano , Angioplastia Coronaria con Balón/métodos , Angioplastia Coronaria con Balón/estadística & datos numéricos , Toma de Decisiones , Femenino , Humanos , Relaciones Interprofesionales , Masculino , Persona de Mediana Edad , Revascularización Miocárdica/estadística & datos numéricos , Grupo de Atención al Paciente/organización & administración , Selección de Paciente , Pautas de la Práctica en Medicina/estadística & datos numéricos , Estudios Prospectivos , Derivación y ConsultaRESUMEN
INTRODUCTION: Maraviroc inhibits CCR5-tropic HIV-1 across different subtypes in vitro and has demonstrated efficacy in clinical trials. V3-loop amino acid variants observed in individual maraviroc-resistant viruses have not been found to be predictive of reduced susceptibility. Sequence-database searches have demonstrated that approximately 7.3% of viruses naturally encode these variants, raising concerns regarding potential pre-existing resistance. A study from Russia reported that combinations of these same amino acids are present in the V3 loops of the Russian variant subtype A (IDU-A, now A6) with a much greater prevalence (range: 74.4%-92.3%) depending on the combination. However, these studies and database searches did not include phenotypic evaluation. METHODS: Sixteen Russian HIV-1 isolates (including sub-subtype A6 viruses) were assessed for V3 loop sequence and phenotypic susceptibility to maraviroc. RESULTS: All 12 of the A6 viruses and 2/4 subtype B isolates encoded V3-loop variants that have previously been identified in individual virus isolates with reduced susceptibility to maraviroc. However, despite the prevalence of these V3-loop amino acid variants among the tested viruses, phenotypic sensitivity to maraviroc was observed in all instances. Similarly, reduced susceptibility to maraviroc was not found in virus from participants who experienced virologic failure in a clinical study of maraviroc in Russia (A4001101, [NCT01275625]). DISCUSSION: Altogether, these data confirm that the presence of individual or combinations of V3-loop amino acid residues in sub-subtype A6 viruses alone does not predict natural resistance to maraviroc and that V3-loop genotype analysis of R5 virus prior to treatment is not helpful in predicting clinical outcome.
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Infecciones por VIH , Seropositividad para VIH , VIH-1 , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Maraviroc , Federación de RusiaRESUMEN
Viruses from 15 of 35 maraviroc-treated participants with virologic failure and CCR5-tropic (R5) virus in the MOTIVATE studies at Week 24 had reduced maraviroc susceptibility. On-treatment amino acid changes were observed in the viral envelope glycoprotein 120 third variable (V3)-loop stems and tips and differed between viruses. No amino acid change reliably predicted reduced susceptibility, indicating that resistance was genetic context-dependent. Through Week 24, poor adherence was associated with maraviroc-susceptible virologic failure, whereas reduced maraviroc susceptibility was associated with suboptimal background regimen activity, highlighting the importance of overall regimen activity and good adherence. Predictive values of pretreatment V3-loop sequences containing these Week 24 mutations or other variants present at >3% in pretreatment viruses of participants with virologic failure at Week 48 were retrospectively assessed. Week 48 clinical outcomes were evaluated for correlates with pretreatment V3-loop CCR5-tropic sequences from 704 participants (366 responders; 338 virologic failures [83 with R5 virus with maraviroc susceptibility assessment]). Seventy-five amino acid variants with >3% prevalence were identified among 23 V3-loop residues. Previously identified variants associated with resistance in individual isolates were represented, but none were associated reliably with virologic failure alone or in combination. Univariate analysis showed virologic-failure associations with variants 4L, 11R, and 19S (P < 0.05). However, 11R is a marker for CXCR4 tropism, whereas neither 4L nor 19S was reliably associated with reduced maraviroc susceptibility in R5 failure. These findings from a large study of V3-loop sequences confirm lack of correlation between V3-loop genotype and clinical outcome in participants treated with maraviroc.Clinical trial registration numbers (ClinicalTrials.gov): NCT00098306 and NCT00098722.
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Infecciones por VIH , VIH-1 , Genotipo , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Maraviroc , Receptores CCR5/genética , Estudios Retrospectivos , Tropismo ViralRESUMEN
Array CGH enables the detection of pathogenic copy number variants (CNVs) in 5-15% of individuals with intellectual disability (ID), making it a promising tool for uncovering ID candidate genes. However, most CNVs encompass multiple genes, making it difficult to identify key disease gene(s) underlying ID etiology. Using array CGH we identified 47 previously unreported unique CNVs in 45/255 probands. We prioritized ID candidate genes using five bioinformatic gene prioritization web tools. Gene priority lists were created by comparing integral genes from each CNV from our ID cohort with sets of training genes specific either to ID or randomly selected. Our findings suggest that different training sets alter gene prioritization only moderately; however, only the ID gene training set resulted in significant enrichment of genes with nervous system function (19%) in prioritized versus non-prioritized genes from the same de novo CNVs (7%, p < 0.05). This enrichment further increased to 31% when the five web tools were used in concert and included genes within mitogen-activated protein kinase (MAPK) and neuroactive ligand-receptor interaction pathways. Gene prioritization web tools enrich for genes with relevant function in ID and more readily facilitate the selection of ID candidate genes for functional studies, particularly for large CNVs.
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Hibridación Genómica Comparativa/métodos , Discapacidad Intelectual/genética , Biología Computacional , Genes , HumanosRESUMEN
BACKGROUND: Autism spectrum disorders (ASDs) are common, heritable neurobiologic conditions of unknown aetiology confounded by significant clinical and genetic heterogeneity. METHODS: This study evaluated a broad categorisation of phenotypic traits (or phenome) for 100 subjects with Autism Diagnostic Interview-Revised/Autism Diagnostic Observation Schedule-Generic (ADI-R/ADOS-G) confirmed idiopathic ASD undergoing 1 Mb bacterial artificial chromosome (BAC) array comparative genomic hybridisation (CGH). RESULTS AND CONCLUSIONS: Array CGH uncovered nine different pathogenic copy number variants (pCNVs) in 9/100 ASD subjects having complex phenotypes (ASD+/- intellectual disability (ID; IQ<70)) and/or physical anomalies), normal karyotype, fragile X analysis, and comprehensive evaluation by a clinical geneticist. Unique pCNVs in our cohort included del(5)(p15.2p15.31) (2.4 Mb), del(3)(p24.3) (0.1 Mb) and dup(18)(p11.3)(0.9 Mb). Five pCNVs were recurrent in our cohort or were previously described in subjects with ASD+/-ID: (dup(7)(q11.23)(1.5 Mb); del(2)(p15p16.1) (6.1 Mb and 7.9 Mb); del(14)(q11.2) (0.7 Mb) and dup(15)(q11q13) (10 Mb), including del(X)(p11.22) (470 Kb) in two autistic brothers. Male: female distribution in subjects with pCNVs was reduced to 1.25:1 from 3.2:1 in the original cohort. The authors stratified the study population according to a broad spectrum of clinical features and correlated specific phenotypes with respect to CNV load and pathogenicity. The findings indicate increased prevalence of pCNVs in subjects with microcephaly (<2nd centile; n = 2 of 4 ASD subjects with microcephaly; p = 0.04), and ID (n = 9 of 64 subjects with ASD and ID; p = 0.02). Interestingly, in the absence of ID co-morbidity with an ASD, no pCNVs were found. The relationship between parental ages at delivery and CNV load and pathogenicity was also explored.
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Trastornos Generalizados del Desarrollo Infantil/genética , Variación Genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Dosificación de Gen , Genotipo , Humanos , Masculino , FenotipoRESUMEN
The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P<0.01), notably depth-wise in the supra- and periorbital regions anterior to the frontal pole of the right hemisphere of the brain. Unaffected mothers of children with ASD display similar significant facial asymmetry, more exaggerated than that in matched controls (P<0.03) and, in particular, show vertical asymmetry of the periorbital region. Unaffected fathers of children with ASD did not show facial asymmetry to a significant degree compared to controls. Two thirds of unaffected male siblings tested were classified unseen as more facially similar to unrelated boys with ASD than to unrelated controls. These unaffected male siblings and two small groups of girls with ASD and female siblings, all show overall directional asymmetry, but without achieving statistical significance in two-tailed t-tests of individual asymmetry of ASD family and matched control groups. We conclude that previously identified right dominant asymmetry of the frontal poles of boys with ASD could explain their facial asymmetry through the direct effect of brain growth. The atypical facial asymmetry of unaffected mothers of children with ASD requires further brain studies before the same explanation can be proposed. An alternative explanation, not mutually exclusive, is a simultaneous and parallel action on face and brain growth by genetic factors. Both possibilities suggest the need for coordinated face and brain studies on ASD probands and their first-degree relatives, especially on unaffected mothers, given that their unusual facial asymmetry suggests an ASD susceptibility arising from maternal genes.
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Trastorno Autístico/genética , Encéfalo/anatomía & histología , Cara/anatomía & histología , Asimetría Facial/genética , Expresión Facial , Adolescente , Adulto , Niño , Preescolar , Femenino , Historia del Siglo XVII , Humanos , Masculino , Madres , HermanosRESUMEN
In order to obtain information on the possible functions of endogenous opiates in the primate cerebral cortex, we assessed the distribution of mu-like opiate receptors (which selectively bind 3H-labeled naloxone) and delta-like opiate receptors (which selectively bind 3H-labeled D-Ala2, D-Leu5-enkephalin) throughout the cerebral cortex of the rhesus monkey. Stereospecific [3H]naloxone binding sites increased in a gradient along hierarchically organized cortical systems that sequentially process modality-specific sensory information of a progressively more complex nature. Specific [3H]enkephalin binding sites, in contrast, were relatively evenly distributed throughout the cerebral cortex. These results, in combination with electrophysiological studies of monkeys and humans, suggest that mu-like opiate receptors may play a role in the affective filtering of sensory stimuli at the cortical level, that is, in emotion-induced selective attention.
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Corteza Cerebral/metabolismo , Receptores Opioides/metabolismo , Animales , Corteza Auditiva/metabolismo , Mapeo Encefálico , Encefalinas/metabolismo , Femenino , Macaca mulatta , Masculino , Naloxona/metabolismo , Corteza Visual/metabolismoRESUMEN
Putatively benign copy number variants (bCNVs) can be broadly defined as DNA copy number gains or losses that do not lead to a recognizable clinical phenotype. Detection of bCNVs in genomes of clinically healthy individuals is increasing with the widespread use of whole genome arrays of different resolutions and the use of sequence comparison methods. However, the role of bCNVs in human disease susceptibility and phenotype diversity is mostly unknown. In order to explore a potential role of bCNVs in the susceptibility to and/or pathogenesis of human neurodevelopmental disorders we examined the frequency and type of common bCNVs (detected in >/=2 independent control studies) amongst 221 subjects with an autism spectrum disorder (ASD) and/or intellectual disability (ID) in comparison to 40 controls using three array platforms of increasing resolution (Spectral Genomics (1 Mb), Agilent (0.03 Mb) and NimbleGen (0.01 Mb)). We determined that the number of bCNVs/subject, type and frequency of most common bCNVs were similar for both the test and control cohorts when the same array platform was used. The comparison of the 'load' of bCNVs (i.e. number/subject) to a standardized metric of phenotypic features (see de Vries et al., 2001) in 91 ASD subjects revealed that a phenotype score >/=4 is significantly more common (P < 0.05) in persons with an ASD having one or more bCNVs via 1 Mb array-CGH, whereas individuals without any recognizable bCNVs are significantly more likely to have a less complex phenotype and a score =3. Finally, we report 14 CNVs found amongst our ASD and ID cohorts that are infrequent in neurodevelopmentally normal controls and are of familial origin, thus comprising rare CNVs of unknown significance. Two of these rare familial bCNVs revealed variation in size when transmitted from parent to child, indicating genomic instability. The ongoing discovery and correlation of the pathogenic versus putatively benign underpinnings of the human genome, its inherent variability and potential gene, positional and epigenetic influences will continue to improve our understanding of genome plasticity and its influences on human neurodevelopmental disorders.