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3.
Autism Res ; 13(3): 474-488, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31957984

RESUMO

The objective of this study was to establish a large, densely sampled, U.S. population-based cohort of people with autism spectrum disorder (ASD). The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by ASD. Diagnosis was based on direct behavioral observation via the Autism Diagnostic Observation Schedule, Second Edition. For the first 1,000 participants, ages ranged from 21 months to 64 years. Using Geographic Information System and published prevalence rates, the overall cohort is estimated to represent between 20% and 49% of pediatric age persons in Rhode Island with ASD, with demographics representative of U.S. Census. We observed a high rate of co-occurring medical and psychiatric conditions in affected individuals. Among the most prominent findings of immediate clinical importance, we found that females received a first diagnosis of ASD at a later age than males, potentially due to more advanced language abilities in females with ASD. In summary, this is the first analysis of a large, population-based U.S. cohort with ASD. Given the depth of sampling, the RI-CART study reflects an important new resource for studying ASD in a representative U.S. population. Psychiatric and medical comorbidities in ASD constitute a substantial burden and warrant adequate attention as part of overall treatment. Our study also suggests that new strategies for earlier diagnosis of ASD in females may be warranted. Autism Res 2020, 13: 474-488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by autism spectrum disorder (ASD). In this article, we provide results from the first 1,000 participants, estimated to represent >20% of affected families in the state. Importantly, we find a later age at first diagnosis of ASD in females, which potentially calls attention to the need for improved early diagnosis in girls. Also, we report a high rate of co-occurring medical and psychiatric conditions in affected individuals.

4.
Behav Sci Law ; 37(5): 512-521, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31389076

RESUMO

Trisomy 20 is a genetic abnormality in which individuals have an extra copy of chromosome 20. Complete trisomy 20 is rare and believed to be incompatible with life. A mosaic form of trisomy 20, in which only some cells or tissues contain the extra chromosome, is a relatively commonly encountered chromosomal abnormality found during prenatal testing, and c. 90% result in a normal phenotype. However, despite the absence of a consistent phenotype, certain findings have been reported across multiple cases of mosaic trisomy 20. These include an array of morphological findings, developmental delays, and learning disabilities. Beyond physical manifestations, a wide range of developmental and learning delays have also been reported. In this work, we provide an overview of the trisomy 20 literature and a case report of a young adult male with mosaic trisomy 20 who committed homicide. His developmental and life history, eventual diagnosis of mosaic trisomy 20, similarities and differences in his condition compared with prior research findings, and potentially new phenotypic findings associated with trisomy 20 that he manifested (childhood visual hallucinations, self-injury, polydactyly) are presented. Additionally, the potential role of this genetic diagnosis in his neuropsychiatric history and its successful application as a mitigating factor at his capital sentencing trial are described. We did not identify other similar cases during our search of major scientific and legal databases. As a backdrop, the use of genetics in criminal trials is on the rise, and courts are increasingly likely to accept behavioral genetics evidence; therefore, it is crucial that the legal system is well acquainted with the opportunities and limitations of these approaches.


Assuntos
Direito Penal , Homicídio/psicologia , Transtornos Mentais/psicologia , Mosaicismo , Trissomia/fisiopatologia , Sobreviventes Adultos de Maus-Tratos Infantis , Cromossomos Humanos Par 20/genética , Criptorquidismo/genética , Criptorquidismo/fisiopatologia , Exposição à Violência , Psiquiatria Legal , Genética Comportamental , Alucinações/genética , Alucinações/fisiopatologia , Alucinações/psicologia , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/psicologia , Masculino , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Fenótipo , Polidactilia/genética , Polidactilia/fisiopatologia , Escoliose/genética , Escoliose/fisiopatologia , Trissomia/genética , Adulto Jovem
8.
J Clin Psychiatry ; 80(1)2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30549495

RESUMO

The International Society of Psychiatric Genetics (ISPG) created a Residency Education Committee with the purpose of identifying key genetic knowledge that should be taught in psychiatric training programs. Thirteen committee members were appointed by the ISPG Board of Directors, based on varied training, expertise, gender, and national origin. The Committee has met quarterly for the past 2 years, with periodic reports to the Board and to the members of the Society. The information summarized includes the existing literature in the field of psychiatric genetics and the output of ongoing large genomics consortia. An outline of clinically relevant areas of genetic knowledge was developed, circulated, and approved. This document was expanded and annotated with appropriate references, and the manuscript was developed. Specific information regarding the contribution of common and rare genetic variants to major psychiatric disorders and treatment response is now available. Current challenges include the following: (1) Genetic testing is recommended in the evaluation of autism and intellectual disability, but its use is limited in current clinical practice. (2) Commercial pharmacogenomic testing is widely available, but its utility has not yet been clearly established. (3) Other methods, such as whole exome and whole genome sequencing, will soon be clinically applicable. The need for informed genetic counseling in psychiatry is greater than ever before, knowledge in the field is rapidly growing, and genetic education should become an integral part of psychiatric training.


Assuntos
Internato e Residência/métodos , Transtornos Mentais/genética , Psiquiatria/educação , Genética/educação , Genética/ética , Humanos , Transtornos Mentais/tratamento farmacológico , Psicotrópicos/uso terapêutico , Sociedades Médicas
10.
Genes Cells ; 22(5): 436-451, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28370817

RESUMO

Duplications of human chromosome 2q13 have been reported in patients with neurodevelopmental disorder including autism spectrum disorder. Nephronophthisis-1 (NPHP1) was identified as a causative gene in the minimal deletion on chromosome 2q13 for familial juvenile type 1 nephronophthisis and Joubert syndrome, an autosomal recessive neurodevelopmental disorder characterized by a cerebellar and brain stem malformation, hypotonia, developmental delay, ataxia, and sometimes associated with cognitive impairment. NPHP1 encodes a ciliary protein, nephrocystin-1, which is expressed in the brain, yet its function in the brain remains largely unknown. In this study, we generated bacterial artificial chromosome-based transgenic mice, called 2q13 dup, that recapitulate human chromosome 2q13 duplication and contain one extra copy of the Nphp1 transgene. To analyze any behavioral alterations in 2q13 dup mice, we conducted a battery of behavioral tests. Although 2q13 dup mice show no significant differences in social behavior, they show deficits in spontaneous alternation behavior and fear memory. We also carried out magnetic resonance imaging to confirm whether copy number gain in this locus affects the neuroanatomy. There was a trend toward a decrease in the cerebellar paraflocculus of 2q13 dup mice. This is the first report of a genetic mouse model for human 2q13 duplication.


Assuntos
Proteínas de Transporte/genética , Duplicação Cromossômica , Cromossomos/genética , Deficiências do Desenvolvimento/genética , Fenótipo , Comportamento Social , Proteínas Adaptadoras de Transdução de Sinal , Animais , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Cerebelo/fisiopatologia , Proteínas do Citoesqueleto , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Medo , Memória , Camundongos , Camundongos Endogâmicos C57BL
11.
Nat Rev Genet ; 18(6): 362-376, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28260791

RESUMO

Genetic studies have revealed the involvement of hundreds of gene variants in autism. Their risk effects are highly variable, and they are frequently related to other conditions besides autism. However, many different variants converge on common biological pathways. These findings indicate that aetiological heterogeneity, variable penetrance and genetic pleiotropy are pervasive characteristics of autism genetics. Although this advancing insight should improve clinical care, at present there is a substantial discrepancy between research knowledge and its clinical application. In this Review, we discuss the current challenges and opportunities for the translation of autism genetics knowledge into clinical practice.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Transtorno Autístico/terapia , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos
13.
Neuron ; 87(6): 1215-1233, 2015 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-26402605

RESUMO

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Loci Gênicos/genética , Variação Genética/genética , Mapas de Interação de Proteínas/genética , Feminino , Humanos , Masculino
14.
Nature ; 520(7545): 51-6, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25807484

RESUMO

Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Encéfalo/metabolismo , Cateninas/deficiência , Cateninas/genética , Animais , Encéfalo/embriologia , Cateninas/metabolismo , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Variações do Número de Cópias de DNA/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Exoma/genética , Feminino , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/patologia , Humanos , Masculino , Camundongos , Modelos Genéticos , Herança Multifatorial/genética , Mutação de Sentido Incorreto , Rede Nervosa , Neurônios/citologia , Neurônios/metabolismo , Caracteres Sexuais , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
15.
JAMA Psychiatry ; 72(2): 119-26, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25493922

RESUMO

IMPORTANCE: Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood. OBJECTIVES: To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs. DESIGN, SETTING, AND PARTICIPANTS: Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project. MAIN OUTCOMES AND MEASURES: We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison. RESULTS: A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07). CONCLUSIONS AND RELEVANCE: Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children's developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders.


Assuntos
Transtorno Autístico/fisiopatologia , Transtornos Cromossômicos/fisiopatologia , Deficiência Intelectual/fisiopatologia , Inteligência/genética , Pais , Fenótipo , Desempenho Psicomotor/fisiologia , Comportamento Social , Adulto , Transtorno Autístico/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Irmãos
16.
Biol Psychiatry ; 77(9): 775-84, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25534755

RESUMO

BACKGROUND: Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. METHODS: Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. RESULTS: Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. CONCLUSIONS: In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Fenótipo , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Família , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
17.
Autism Res ; 7(3): 355-62, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24821083

RESUMO

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Adulto , Criança , Feminino , Humanos , Masculino
18.
Biol Psychiatry ; 74(8): 576-84, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23746936

RESUMO

BACKGROUND: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. METHODS: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. RESULTS: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. CONCLUSIONS: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.


Assuntos
Transtorno Autístico/patologia , Cabeça/patologia , Característica Quantitativa Herdável , Adulto , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Pesos e Medidas Corporais , Criança , Família , Feminino , Humanos , Inteligência/fisiologia , Masculino
19.
Lancet Neurol ; 12(4): 406-14, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23518333

RESUMO

Neurodevelopmental disorders can be caused by many different genetic abnormalities that are individually rare but collectively common. Specific genetic causes, including certain copy number variants and single-gene mutations, are shared among disorders that are thought to be clinically distinct. This evidence of variability in the clinical manifestations of individual genetic variants and sharing of genetic causes among clinically distinct brain disorders is consistent with the concept of developmental brain dysfunction, a term we use to describe the abnormal brain function underlying a group of neurodevelopmental and neuropsychiatric disorders and to encompass a subset of various clinical diagnoses. Although many pathogenic genetic variants are currently thought to be variably penetrant, we hypothesise that when disorders encompassed by developmental brain dysfunction are considered as a group, the penetrance will approach 100%. The penetrance is also predicted to approach 100% when the phenotype being considered is a specific trait, such as intelligence or autistic-like social impairment, and the trait could be assessed using a continuous, quantitative measure to compare probands with non-carrier family members rather than a qualitative, dichotomous trait and comparing probands with the healthy population.


Assuntos
Encefalopatias/diagnóstico , Encefalopatias/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Animais , Transtorno Autístico/diagnóstico , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Encefalopatias/epidemiologia , Deficiências do Desenvolvimento/epidemiologia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/genética
20.
Mol Autism ; 3(1): 9, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23067556

RESUMO

BACKGROUND: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. METHODS: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. RESULTS: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. CONCLUSIONS: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.

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