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1.
Cell ; 149(3): 525-37, 2012 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-22521361

RESUMO

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Aberrações Cromossômicas , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Quebra Cromossômica , Deleção Cromossômica , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Sistema Nervoso/crescimento & desenvolvimento , Esquizofrenia/genética , Análise de Sequência de DNA , Transdução de Sinais
2.
J Assist Reprod Genet ; 39(11): 2483-2504, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36422765

RESUMO

PURPOSE: This preclinical study aimed to evaluate whether using transferred mosaic embryos (primarily selected by embryonic morphology assessment (EMA) and compared by the noninvasive preimplantation genetic testing for aneuploidy (niPGT-A) on cell-free DNA in blastocoel fluid (BF)) increases the rates of clinical pregnancies (CPs) and healthy live births (HLBs) and to investigate whether niPGT-A could provide valuable genetic information for the EMA-selected transferred mosaic embryos. METHODS: This study collected 215 blastocyst culture samples and 182 BF samples. Cell-free DNA from the BF was amplified and examined by next-generation sequencing-based niPGT-A. All 182 patients underwent EMA. However, only 147 underwent in vitro fertilization and embryo transfer, and only 113 clinical outcomes were followed up. Comprehensive chromosome screening for the chorionic villus sampling of spontaneous miscarriages and noninvasive prenatal testing for ongoing pregnancies were also performed. RESULTS: The implantation rate was 77.55% in 147 transferred high-quality embryos selected by EMA. Among 113 CPs, 16 led to spontaneous miscarriage (14.16%), and 97 resulted in HLBs (85.84%). According to the niPGT-A results for 113 patients with clinical outcomes, 80.4% had CP (euploid, 20.54%; single aneuploid, 1.79%; mosaic chromosome aneuploid and/or segmental aneuploid, 58.04%). Of all the mosaic aneuploids, 90.76% were false positive, transforming to euploid. CONCLUSIONS: Transferred EMA-selected embryos showed higher implantation rates. The niPGT-A of BF provided valuable genetic status ("-ploid") information, which helped reduce aneuploid-induced implantation failure and miscarriage, thereby increasing the CP and HLB rates. Additionally, majority of the transferred embryos with complex/chaotic mosaic aneuploid would likely develop HLBs.


Assuntos
Aborto Espontâneo , Ácidos Nucleicos Livres , Diagnóstico Pré-Implantação , Gravidez , Feminino , Humanos , Diagnóstico Pré-Implantação/métodos , Nascido Vivo/genética , Ácidos Nucleicos Livres/genética , Aborto Espontâneo/genética , Blastocisto , Aneuploidia , Testes Genéticos/métodos , Fertilização in vitro
3.
Hum Mutat ; 38(4): 378-389, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27925688

RESUMO

Increasing evidence that mutation of planar cell polarity (PCP) genes contributes to human cranial neural tube defect (NTD) susceptibility prompted us to hypothesize that rare variants of genes in the core apical-basal polarity (ABP) pathway are risk factors for cranial NTDs. In this study, we screened for rare genomic variation of PARD3 in 138 cranial NTD cases and 274 controls. Overall, the rare deleterious variants of PARD3 were significantly associated with increased risk for cranial NTDs (11/138 vs.7/274, P < 0.05, OR = 3.3). These NTD-specific variants were significantly enriched in the aPKC-binding region (6/138 vs. 0/274, P < 0.01). The East Asian cohort in the ExAC database and another Chinese normal cohort further supported this association. Over-expression analysis in HEK293T and MDCK cells confirmed abnormal aPKC binding or interaction for two PARD3 variants (p.P913Q and p.D783G), resulting in defective tight junction formation via disrupted aPKC binding. Functional analysis in human neural progenitor cells and chick embryos revealed that PARD3 knockdown gave rise to abnormal cell polarity and compromised the polarization process of neuroepithelial tissue. Our studies suggest that rare deleterious variants of PARD3 in the aPKC-binding region contribute to human cranial NTDs, possibly by disrupting apical tight junction formation and subsequent polarization process of the neuroepithelium.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Membrana/genética , Mutação , Defeitos do Tubo Neural/genética , Proteína Quinase C/metabolismo , Junções Íntimas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Povo Asiático/genética , Padronização Corporal/genética , Proteínas de Ciclo Celular/metabolismo , Embrião de Galinha , China , Estudos de Coortes , Cães , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Proteínas de Membrana/metabolismo , Defeitos do Tubo Neural/etnologia , Defeitos do Tubo Neural/metabolismo , Ligação Proteica , Interferência de RNA , Junções Íntimas/patologia
4.
N Engl J Med ; 371(8): 733-43, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25140959

RESUMO

BACKGROUND: Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. METHODS: Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. RESULTS: Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. CONCLUSIONS: Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).


Assuntos
Córtex Cerebral/anormalidades , Análise Mutacional de DNA/métodos , Malformações do Desenvolvimento Cortical/genética , Mutação , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Humanos , Lisencefalia/genética , Imageamento por Ressonância Magnética , Malformações do Desenvolvimento Cortical/patologia , Heterotopia Nodular Periventricular/genética
5.
Nature ; 478(7367): 97-102, 2011 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-21881559

RESUMO

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.


Assuntos
Índice de Massa Corporal , Cromossomos Humanos Par 16/genética , Dosagem de Genes/genética , Obesidade/genética , Fenótipo , Magreza/genética , Adolescente , Adulto , Idoso , Envelhecimento , Estatura/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Metabolismo Energético/genética , Europa (Continente) , Feminino , Duplicação Gênica/genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Cabeça/anatomia & histologia , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos Mentais/genética , Pessoa de Meia-Idade , Mutação/genética , América do Norte , RNA Mensageiro/análise , RNA Mensageiro/genética , Deleção de Sequência/genética , Transcrição Gênica , Adulto Jovem
6.
Pflugers Arch ; 468(8): 1311-32, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27125215

RESUMO

Genetic deficiency of the SLC26A1 anion exchanger in mice is known to be associated with hyposulfatemia and hyperoxaluria with nephrolithiasis, but many aspects of human SLC26A1 function remain to be explored. We report here the functional characterization of human SLC26A1, a 4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid (DIDS)-sensitive, electroneutral sodium-independent anion exchanger transporting sulfate, oxalate, bicarbonate, thiosulfate, and (with divergent properties) chloride. Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs in its stimulation by alkaline pHo and inhibition by acidic pHo but not pHi and in its failure to transport glyoxylate. SLC26A1-mediated transport of sulfate and oxalate is highly dependent on allosteric activation by extracellular chloride or non-substrate anions. Extracellular chloride stimulates apparent V max of human SLC26A1-mediated sulfate uptake by conferring a 2-log decrease in sensitivity to inhibition by extracellular protons, without changing transporter affinity for extracellular sulfate. In contrast to SLC26A1-mediated sulfate transport, SLC26A1-associated chloride transport is activated by acid pHo, shows reduced sensitivity to DIDS, and exhibits cation dependence of its DIDS-insensitive component. Human SLC26A1 resembles SLC26 paralogs in its inhibition by phorbol ester activation of protein kinase C (PKC), which differs in its undiminished polypeptide abundance at or near the oocyte surface. Mutation of SLC26A1 residues corresponding to candidate anion binding site-associated residues in avian SLC26A5/prestin altered anion transport in patterns resembling those of prestin. However, rare SLC26A1 polymorphic variants from a patient with renal Fanconi Syndrome and from a patient with nephrolithiasis/calcinosis exhibited no loss-of-function phenotypes consistent with disease pathogenesis.


Assuntos
Proteínas de Transporte de Ânions/metabolismo , Ânions/metabolismo , Cloretos/metabolismo , Animais , Proteínas de Transporte de Ânions/genética , Bicarbonatos/metabolismo , Transporte Biológico/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Transporte de Íons/fisiologia , Mutação/genética , Oócitos/metabolismo , Oxalatos/metabolismo , Proteína Quinase C/metabolismo , Transportadores de Sulfato , Sulfatos/metabolismo , Tiossulfatos/metabolismo , Xenopus/metabolismo
7.
Am J Hum Genet ; 92(3): 375-86, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23472757

RESUMO

NRXN1 microdeletions occur at a relatively high frequency and confer increased risk for neurodevelopmental and neurobehavioral abnormalities. The mechanism that makes NRXN1 a deletion hotspot is unknown. Here, we identified deletions of the NRXN1 region in affected cohorts, confirming a strong association with the autism spectrum and other neurodevelopmental disorders. Interestingly, deletions in both affected and control individuals were clustered in the 5' portion of NRXN1 and its immediate upstream region. To explore the mechanism of deletion, we mapped and analyzed the breakpoints of 32 deletions. At the deletion breakpoints, frequent microhomology (68.8%, 2-19 bp) suggested predominant mechanisms of DNA replication error and/or microhomology-mediated end-joining. Long terminal repeat (LTR) elements, unique non-B-DNA structures, and MEME-defined sequence motifs were significantly enriched, but Alu and LINE sequences were not. Importantly, small-size inverted repeats (minus self chains, minus sequence motifs, and partial complementary sequences) were significantly overrepresented in the vicinity of NRXN1 region deletion breakpoints, suggesting that, although they are not interrupted by the deletion process, such inverted repeats can predispose a region to genomic instability by mediating single-strand DNA looping via the annealing of partially reverse complementary strands and the promoting of DNA replication fork stalling and DNA replication error. Our observations highlight the potential importance of inverted repeats of variable sizes in generating a rearrangement hotspot in which individual breakpoints are not recurrent. Mechanisms that involve short inverted repeats in initiating deletion may also apply to other deletion hotspots in the human genome.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Variações do Número de Cópias de DNA , Sequências Repetidas Invertidas , Transtornos Mentais/genética , Proteínas do Tecido Nervoso/genética , Deleção de Sequência , Proteínas de Ligação ao Cálcio , Estudos de Coortes , Replicação do DNA/genética , DNA de Forma B/genética , DNA de Cadeia Simples/genética , Éxons , Predisposição Genética para Doença , Instabilidade Genômica , Humanos , Moléculas de Adesão de Célula Nervosa , Sequências Repetidas Terminais
8.
Am J Hum Genet ; 92(2): 210-20, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23332918

RESUMO

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.


Assuntos
Éxons/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteínas/química , Proteínas/genética , Deleção de Sequência/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Proteínas do Citoesqueleto , Fácies , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Fenótipo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Supressão Genética , Síndrome , Fatores de Transcrição , Adulto Jovem , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/genética
9.
J Magn Reson Imaging ; 44(5): 1143-1150, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27015960

RESUMO

PURPOSE: To quantitatively investigate left ventricular volume and function in middle-aged healthy subjects. MATERIALS AND METHODS: Ninety healthy volunteers underwent cardiac 3 Tesla MRI. The left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), cardiac output (CO), myocardial mass (MM), and their normalized indices (EDVI, ESVI, SVI, CI, and MI, respectively) after corrected with the body surface area (BSA) were analyzed and compared at different ages. RESULTS: All subjects had successfully completed the 3-Tesla cardiac MR. Females had significantly smaller EDV (110.5 ± 9.2 versus 125.7 ± 8.3 mL), ESV (36.1 ± 3.5 versus 41.5 ± 3.8 mL), SV (74.3 ± 6.3 versus 84.2 ± 6.7 mL), CO (5.4 ± 0.8 versus 5.8 ± 0.9 l/min) and MM (73.0 ± 10.5 versus 94.8 ± 10.6 g) than males (P < 0.05). The EF had no significant (P = 0.47) difference between genders (67.3 ± 1.7 percent in females versus 66.9 ± 2.4 percent in males). After normalization with BSA, no significant (P > 0.05) difference was detected between the genders in EDVI (71.2 ± 4.3 versus 71.1 ± 4.2 mL/m2 , P = 0.882), ESVI (23.3 ± 1.9 versus 23.5 ± 1.9 mL/m2 , P = 0.733) and SVI (47.9 ± 2.9 versus 47.7 ± 3.7 mL/m2 , P = 0.698) except for CI and MI. Females had significantly (P < 0.05) greater CI (3.5 ± 0.4 versus 3.3 ± 0.4) but smaller MI (46.9 ± 5.3 versus 53.6 ± 7.6) than males. EDV, EDVI, ESV, ESVI, SV, and SVI significantly (P < 0.05) decreased with age increase. BSA was positively correlated with EDV, ESV, SV, MM, and CO. No significance (P > 0.05) was detected in other parameters. CONCLUSION: The left ventricular volume and function differs in women compared with men in the middle-aged population, and these parameters have a tendency of decrease with ageing. J. Magn. Reson. Imaging 2016;44:1143-1150.


Assuntos
Envelhecimento/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Adulto , Distribuição por Idade , Idoso , Envelhecimento/patologia , China/epidemiologia , Feminino , Ventrículos do Coração/anatomia & histologia , Humanos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição por Sexo
10.
Ann Neurol ; 75(6): 943-58, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24811917

RESUMO

OBJECTIVE: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. METHODS: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. RESULTS: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. INTERPRETATION: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.


Assuntos
Transtornos Cromossômicos/complicações , Variações do Número de Cópias de DNA/genética , Epilepsia/etiologia , Epilepsia/genética , Eletroencefalografia , Feminino , Perfilação da Expressão Gênica , Humanos , Classificação Internacional de Doenças , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Estudos Retrospectivos
11.
Int J Mol Sci ; 16(5): 10061-76, 2015 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-25946342

RESUMO

Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential nutrients for brain development and function. However, whether or not the levels of these fatty acids are altered in individuals with autism remains debatable. In this study, we compared the fatty acid contents between 121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3-17. Analysis of the fatty acid composition of red blood cell (RBC) membrane phospholipids showed that the percentage of total PUFA was lower in autistic patients than in controls; levels of n-6 arachidonic acid (AA) and n-3 docosahexaenoic acid (DHA) were particularly decreased (p<0.001). In addition, plasma levels of the pro-inflammatory AA metabolite prostaglandin E2 (PGE2) were higher in a subset of the autistic participants (n=20) compared to controls. Our study demonstrates an alteration in the PUFA profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism.


Assuntos
Ácido Araquidônico/sangue , Transtorno Autístico/sangue , Ácidos Docosa-Hexaenoicos/sangue , Eritrócitos/metabolismo , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinoprostona/sangue , Feminino , Humanos , Metabolismo dos Lipídeos , Masculino
12.
Am J Hum Genet ; 89(6): 751-9, 2011 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-22118881

RESUMO

Height is a model polygenic trait that is highly heritable. Genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with stature, but the role of structural variation in determining height is largely unknown. We performed a genome-wide association study of copy-number variation and stature in a clinical cohort of children who had undergone comparative genomic hybridization (CGH) microarray analysis for clinical indications. We found that subjects with short stature had a greater global burden of copy-number variants (CNVs) and a greater average CNV length than did controls (p < 0.002). These associations were present for lower-frequency (<5%) and rare (<1%) deletions, but there were no significant associations seen for duplications. Known gene-deletion syndromes did not account for our findings, and we saw no significant associations with tall stature. We then extended our findings into a population-based cohort and found that, in agreement with the clinical cohort study, an increased burden of lower-frequency deletions was associated with shorter stature (p = 0.015). Our results suggest that in individuals undergoing copy-number analysis for clinical indications, short stature increases the odds that a low-frequency deletion will be found. Additionally, copy-number variation might contribute to genetic variation in stature in the general population.


Assuntos
Estatura/genética , Variações do Número de Cópias de DNA , Deleção de Genes , Frequência do Gene , Estudo de Associação Genômica Ampla , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Duplicação Gênica , Humanos , Masculino , Herança Multifatorial , Adulto Jovem
13.
Am J Hum Genet ; 89(4): 551-63, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21981781

RESUMO

Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MBD5 coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Cromossomos Humanos Par 2 , Proteínas de Ligação a DNA/genética , Epilepsia/genética , Deleção de Genes , Deficiência Intelectual/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Masculino , Fenótipo , Síndrome
14.
Reprod Biomed Online ; 29(3): 382-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24912415

RESUMO

Excessive triple CGG repeats in the FMR1 gene have been widely associated with premature ovarian failure. The number of AGG interruptions and length of uninterrupted CGG repeats have been correlated with repeat instability on transmission. In this study, FMR1 CGG repeats and AGG interruption status were determined by triplet-primed PCR in 117 premature ovarian failure patients and 82 matched controls. A possible relationship between CGG repeats or AGG interruption and serum FSH concentrations in patients and controls was evaluated. One patient had a premutation allele (73 repeats) (1/117), while no such mutations were observed in controls (0/82). Other patients and all controls had CGG repeats in the normal range. There was no significant difference in the incidence of intermediate mutations of CGG repeats between patients and controls and no relationship between CGG repeats with serum FSH concentrations. Interestingly, more individuals with premature ovarian failure carried no AGG interruptions than the controls (4.27% versus 1.83%) but statistical significance was not reached. This small case-control study failed to find associations between CGG repeat sizes or AGG interruptions in FMR1 and premature ovarian failure in Chinese women. Further study with large sample size is warranted.


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Insuficiência Ovariana Primária/genética , Adulto , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , China , Feminino , Humanos , Repetições de Trinucleotídeos
15.
Genet Med ; 15(9): 706-12, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23558256

RESUMO

PURPOSE: A combination of oligonucleotide and single-nucleotide polymorphism probes on the same array platform can detect copy-number abnormalities and copy-neutral aberrations such as uniparental disomy and long stretches of homozygosity. The single-nucleotide polymorphism probe density in commercially available platforms varies widely, which may affect the detection of copy-neutral abnormalities. METHODS: We evaluated the ability of array platforms with low (Oxford Gene Technology CytoSure ISCA uniparental disomy), mid-range (Agilent custom array), and high (Affymetrix CytoScan HD) single-nucleotide polymorphism probe density to detect copy-number variation, mosaicism, uniparental isodisomy, and absence of heterozygosity in 50 clinical samples. RESULTS: All platforms reliably detected copy-number variation, mosaicism, and uniparental isodisomy; however, absence-of-heterozygosity detection varied significantly. The low-density array called absence-of-heterozygosity regions not confirmed by the other platforms and also overestimated the length of true absence-of-heterozygosity regions. Furthermore, the low- and mid-density platforms failed to detect some small absence-of-heterozygosity regions that were identified by the high-density platform. CONCLUSION: Variation in single-nucleotide polymorphism density can lead to major discrepancies in the detection of and confidence in copy-neutral abnormalities. Although suitable for uniparental disomy detection, copy-number plus single-nucleotide polymorphism arrays with 30,000 or fewer unique single-nucleotide polymorphism probes miscall absence-of-heterozygosity regions due to identity by descent.


Assuntos
Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Perda de Heterozigosidade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Polimorfismo de Nucleotídeo Único , Aberrações Cromossômicas , Consanguinidade , Sondas de DNA , Feminino , Genoma Humano , Voluntários Saudáveis , Homozigoto , Humanos , Masculino , Dissomia Uniparental/genética
16.
Am J Med Genet B Neuropsychiatr Genet ; 162B(8): 832-40, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24019301

RESUMO

20p13 telomeric/subtelomeric deletions are clinically significant but are currently under-investigated. So far only five molecularly delineated cases have been reported in literature and no candidate genes have been sufficiently implicated. Here, we present six new deletion cases identified by chromosomal microarray analysis (CMA). We also review 32 cases combined from literature and databases. We found that most 20p13 deletion patients exhibit significant developmental delay. Dysmorphic features are common but a consistent pattern was not recognized. Reduced cognitive ability was frequent. Based on pathogenic deletions delineated in this study, we mapped the smallest overlapping region and identified two nervous system expressing genes (SOX12 and NRSN2) as candidate genes that may be involved in the developmental defects in 20p13 microdeletion.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Fatores de Transcrição SOXC/genética , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Genoma Humano/genética , Humanos , Masculino
17.
Medicine (Baltimore) ; 102(15): e33549, 2023 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-37058049

RESUMO

This study investigated the correlation between 3-Tesla magnetic resonance imaging (MRI) and 256 multiple-slice computed tomography (MSCT) or 2-dimensional echocardiography (ECHO) in evaluating left ventricle. Forty patients were retrospectively enrolled to undergo cardiac MSCT, 3-Tesla MRI and 2-dimensional ECHO within 1 week. The end-diastolic (EDV) and end-systolic volume (ESV), stroke volume (SV) and ejection fraction (EF) were analyzed and compared. MSCT was highly significantly correlated with MRI. Compared with MRI, MSCT slightly overestimated ESV for about 8.7 mL, but slightly underestimated EF and SV for about 6.8% and 5.8 mL, respectively. A high consistency existed between MSCT and MRI, with the 95% limit of agreement (-19.6, 25.4) mL for EDV, (-2.6,20.1) mL for ESV, (-28.3,16.6) mL for SV, and (-18.8%,5.1) % for EF. ECHO was also significantly correlated with MRI. The ECHO slightly underestimated the left ventricular function compared with MRI, with an underestimation of 9.4 mL for EDV, 3.5 mL for ESV, 5.8 mL for SV and 1.0% for EF. A wider agreement limit existed between MRI and ECHO. MSCT has a better correlation and agreement relationship with MRI parameters than 2-dimensional ECHO in assessing the left ventricle and may serve as a possible alternative to MRI.


Assuntos
Ventrículos do Coração , Tomografia Computadorizada por Raios X , Humanos , Ventrículos do Coração/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Imageamento por Ressonância Magnética , Função Ventricular Esquerda , Volume Sistólico , Ecocardiografia
18.
Hum Mutat ; 33(10): 1450-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22610794

RESUMO

Neural tube defects (NTDs) constitute the second most frequent cause of human congenital abnormalities. Complex multigenetic causes have been suggested to contribute to NTDs. The planar cell polarity (PCP) pathway plays a critical role in neural tube closure in model organisms and in human. Knockout of Dact1 (Dapper, Frodo) leads to deregulated PCP signaling with defective neural tube in mice. Here, we report that five missense heterozygote mutations of the DACT1 gene are specifically identified in 167 stillborn or miscarried Han Chinese fetuses with neural tube defects. Our biochemical analyses revealed that among the five mutations, N356K and R45W show loss-of-function or reduced activities in inducing Dishevelled2 (DVL2) degradation and inhibiting jun-N-terminal kinase (JNK) phosphorylation, implicating mutated DACT1 as a risk factor for human NTDs. Our findings, together with early reports, suggest that rare mutations of the PCP-related genes may constitute a great contribution to human NTDs.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação , Defeitos do Tubo Neural/genética , Proteínas Nucleares/genética , Animais , Povo Asiático , Polaridade Celular/genética , Embrião de Mamíferos/metabolismo , Humanos , Camundongos , Camundongos Knockout
20.
Epilepsia ; 53(8): e146-50, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22690784

RESUMO

Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants genome-wide and long-range polymerase chain reaction to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCß1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.


Assuntos
Epilepsias Parciais/genética , Deleção de Genes , Fosfolipase C beta/genética , Homozigoto , Humanos , Lactente , Masculino , Linhagem
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