Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Nat Genet ; 51(7): 1092-1098, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31209396

RESUMO

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2-4 and rare de novo variants5-10 in ASD. Recessive mutations have also been implicated11-14 but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.

3.
Cell Rep ; 26(5): 1112-1127.e9, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699343

RESUMO

The molecular basis of the earliest neuronal changes that lead to Alzheimer's disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD.

4.
Am J Hum Genet ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30503522

RESUMO

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

5.
Cell Rep ; 24(4): 973-986.e8, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30044992

RESUMO

Endosomal sorting complex required for transport (ESCRT) complex proteins regulate biogenesis and release of extracellular vesicles (EVs), which enable cell-to-cell communication in the nervous system essential for development and adult function. We recently showed human loss-of-function (LOF) mutations in ESCRT-III member CHMP1A cause autosomal recessive microcephaly with pontocerebellar hypoplasia, but its mechanism was unclear. Here, we show Chmp1a is required for progenitor proliferation in mouse cortex and cerebellum and progenitor maintenance in human cerebral organoids. In Chmp1a null mice, this defect is associated with impaired sonic hedgehog (Shh) secretion and intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs). Furthermore, we show CHMP1A is important for release of an EV subtype that contains AXL, RAB18, and TMED10 (ART) and SHH. Our findings show CHMP1A loss impairs secretion of SHH on ART-EVs, providing molecular mechanistic insights into the role of ESCRT proteins and EVs in the brain.

6.
Nat Methods ; 15(8): 611-616, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30013045

RESUMO

The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits.

7.
Genome Med ; 10(1): 31, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29673390

RESUMO

We describe a method that enables the multiplex screening of a pool of many different donor cell lines. Our method accurately predicts each donor proportion from the pool without requiring the use of unique DNA barcodes as markers of donor identity. Instead, we take advantage of common single nucleotide polymorphisms, whole-genome sequencing, and an algorithm to calculate the proportions from the sequencing data. By testing using simulated and real data, we showed that our method robustly predicts the individual proportions from a mixed-pool of numerous donors, thus enabling the multiplexed testing of diverse donor cells en masse.More information is available at https://pgpresearch.med.harvard.edu/poolseq/.


Assuntos
Linfócitos B/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Doadores de Tecidos , Sequenciamento Completo do Genoma , Algoritmos , Simulação por Computador , Genoma Humano , Humanos , Polimorfismo de Nucleotídeo Único/genética , Tamanho da Amostra
8.
Nat Neurosci ; 20(9): 1217-1224, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28714951

RESUMO

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.


Assuntos
Transtorno do Espectro Autista/genética , Bases de Dados Genéticas/tendências , Variação Genética/genética , Mutação de Sentido Incorreto/genética , Predisposição Genética para Doença/genética , Humanos , Mosaicismo , Zigoto/fisiologia
9.
Sci Rep ; 7: 46148, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28387241

RESUMO

The Personal Genome Project (PGP) is an effort to enroll many participants to create an open-access repository of genome, health and trait data for research. However, PGP participants are not enrolled for studying any specific traits and participants choose the phenotypes to disclose. To measure the extent and willingness and to encourage and guide participants to contribute phenotypes, we developed an algorithm to score and rank the phenotypes and participants of the PGP. The scoring algorithm calculates the participation index (P-index) for every participant, where 0 indicates no reported phenotypes and 100 indicate complete phenotype reporting. We calculated the P-index for all 5,015 participants in the PGP and they ranged from 0 to 96.7. We found that participants mainly have either high scores (P-index > 90, 29.5%) or low scores (P-index < 10, 57.8%). While, there are significantly more males than female participants (1,793 versus 1,271), females tend to have on average higher P-indexes (P = 0.015). We also reported the P-indexes of participants based on demographics and states like Missouri and Massachusetts have better P-indexes than states like Utah and Minnesota. The P-index can therefore be used as an unbiased way to measure and rank participant's phenotypic contribution towards the PGP.


Assuntos
Fenótipo , Algoritmos , Estudos de Coortes , Doença , Feminino , Genoma Humano , Geografia , Humanos , Masculino , Característica Quantitativa Herdável , Inquéritos e Questionários , Estados Unidos
10.
Am J Hum Genet ; 96(5): 695-708, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25865494

RESUMO

Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r(2) ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10(-8)) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10(-40)). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases.


Assuntos
Estatura/genética , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Adulto , Afro-Americanos/genética , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Ossos da Perna/crescimento & desenvolvimento , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
11.
Ann Neurol ; 78(1): 115-27, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25914168

RESUMO

OBJECTIVE: A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity. METHODS: We performed a genome-wide association study in interferon-ß (IFNß)-treated MS patients followed by validation in 3 independent cohorts. The role of the validated variant was examined in several RNA data sets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro. RESULTS: We found an association between rs9828519(G) and nonresponse to IFNß (pdiscovery = 4.43 × 10(-8)) and confirmed it in a meta-analysis across 3 replication data sets (preplication = 7.78 × 10(-4)). Only 1 gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knockdown in T cells in vitro leads an increase in expression of IFNγ, which is a proinflammatory molecule. INTERPRETATION: This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNß-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na(+) -H(+) exchanger found in endosomes, appears to influence the differentiation of T cells to a proinflammatory fate and may have a broader role in MS disease activity, outside of IFNß treatment.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Citocinas/imunologia , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/genética , Trocadores de Sódio-Hidrogênio/genética , Linfócitos T/imunologia , Adolescente , Adulto , Diferenciação Celular/genética , Células Cultivadas , Estudos de Coortes , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Interferon beta-1a , Interferon beta-1b , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , RNA Interferente Pequeno , Linfócitos T/metabolismo , Adulto Jovem
12.
Eur J Hum Genet ; 23(4): 555-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25370044

RESUMO

Recessive inheritance of gene disrupting alleles, either through homozygosity at a specific site or compound heterozygosity, have been demonstrated to underlie many Mendelian diseases and some complex psychiatric disorders. On the basis of exome sequencing data, an increased burden of complete knockout (homozygous or compound heterozygous) variants has been identified in autism. In addition, using single-nucleotide polymorphism microarray data, an increased rate of homozygosity by descent, or autozygosity, has been linked to the risk of schizophrenia (SCZ). Here, in a large Swedish case-control SCZ sample (11 244 individuals, 5079 of whom have exome sequence data available), we survey the contribution of both autozygosity and complete knockouts to disease risk. We do not find evidence for association with SCZ, either genome wide or at specific loci. However, we note the possible impact of sample size and population genetic factors on the power to detect and quantify any burden that may exist.


Assuntos
Heterozigoto , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Feminino , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Genética Populacional , Homozigoto , Humanos , Modelos Logísticos , Masculino , Esquizofrenia/diagnóstico , Análise de Sequência de DNA , Suécia
13.
Am J Hum Genet ; 95(5): 509-20, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25439097

RESUMO

Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both single-variant and burden testing. Here, we describe a method to improve detection of rare recessive variants in complex diseases termed RAFT (recessive-allele-frequency-based test). We found that RAFT outperforms existing approaches when the variant influences disease risk in a recessive manner on simulated data. We then applied our method to 1,791 Finnish individuals with type 2 diabetes (T2D) and 2,657 matched control subjects. In BBS10, we discovered a rare variant (c.1189A>G [p.Ile397Val]; rs202042386) that confers risk of T2D in a recessive state (p = 1.38 × 10(-6)) and would be missed by conventional methods. Testing of this variant in an established in vivo zebrafish model confirmed the variant to be pathogenic. Taken together, these data suggest that RAFT can effectively reveal rare recessive contributions to complex diseases overlooked by conventional association tests.


Assuntos
Diabetes Mellitus Tipo 2/genética , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Chaperoninas do Grupo II/genética , Modelos Genéticos , Obesidade/genética , Animais , Finlândia , Frequência do Gene , Humanos , Funções Verossimilhança , Razão de Chances , Peixe-Zebra
14.
PLoS Genet ; 10(7): e1004494, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25078778

RESUMO

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹7). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.


Assuntos
Efeito Fundador , Doenças Genéticas Inatas , Deriva Genética , Genética Populacional , Grupo com Ancestrais do Continente Europeu , Exoma/genética , Feminino , Finlândia , Frequência do Gene , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo
15.
Am J Hum Genet ; 94(3): 437-52, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24607388

RESUMO

In most complex diseases, much of the heritability remains unaccounted for by common variants. It has been postulated that lower-frequency variants contribute to the remaining heritability. Here, we describe a method to test for polygenic inheritance from lower-frequency variants by using GWAS summary association statistics. We explored scenarios with many causal low-frequency variants and showed that there is more power to detect risk variants than to detect protective variants, resulting in an increase in the ratio of detected risk to protective variants (R/P ratio). Such an excess can also occur if risk variants are present and kept at lower frequencies because of negative selection. The R/P ratio can be falsely elevated because of reasons unrelated to polygenic inheritance, such as uneven sample sizes or asymmetric population stratification, so precautions to correct for these confounders are essential. We tested our method on published GWAS results and observed a strong signal in some diseases (schizophrenia and type 2 diabetes) but not others. We also explored the shared genetic component in overlapping phenotypes related to inflammatory bowel disease (Crohn disease [CD] and ulcerative colitis [UC]) and diabetic nephropathy (macroalbuminuria and end-stage renal disease [ESRD]). Although the signal was still present when both CD and UC were jointly analyzed, the signal was lost when macroalbuminuria and ESRD were jointly analyzed, suggesting that these phenotypes should best be studied separately. Thus, our method may also help guide the design of future genetic studies of various traits and diseases.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Herança Multifatorial , Albuminúria/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Falência Renal Crônica/genética , Transtornos Mentais/genética , Modelos Estatísticos , Obesidade/genética , Razão de Chances , Fenótipo , Risco
16.
PLoS Genet ; 9(8): e1003671, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23966865

RESUMO

De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Variação Genética , Modelos Teóricos , Mutação , Teorema de Bayes , Estudos de Casos e Controles , Exoma , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Fatores de Risco , Análise de Sequência de DNA
18.
N Engl J Med ; 368(21): 1992-2003, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23656588

RESUMO

BACKGROUND: The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive. METHODS: We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS: Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. CONCLUSIONS: The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).


Assuntos
Ataxia/genética , Demência/genética , Hipogonadismo/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Animais , Consanguinidade , Exoma , Feminino , Humanos , Masculino , Linhagem , Ubiquitina-Proteína Ligases/metabolismo , Peixe-Zebra
19.
Neuron ; 77(2): 235-42, 2013 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-23352160

RESUMO

To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/genética , Demografia/métodos , Deleção de Genes , Perda de Heterozigosidade/genética , Estudos de Casos e Controles , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Pré-Escolar , Cromossomos Humanos X/genética , Feminino , Variação Genética/genética , Homozigoto , Humanos , Desequilíbrio de Ligação/genética , Masculino , Fatores de Risco
20.
Neuron ; 77(2): 259-73, 2013 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-23352163

RESUMO

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Adolescente , Animais , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Linhagem , Ratos , Análise de Sequência de DNA/métodos , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA