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1.
BMC Pregnancy Childbirth ; 21(1): 101, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33516175

RESUMO

BACKGROUND: Monozygotic twins are nearly identical in genotype and phenotype because monozygotic twins arise from one fertilized oocyte. In all cases of discordant karyotype in monozygotic twins, trisomy 21 accounts for about one in 385,000. Monozygotic twins discordant for Robertsonian translocation trisomy 21 of the der (21;21)(q10;q10), in which the additional chromosome originates from the father is rare. CASE PRESENTATION: A 28-year-old parous woman, G3P1A0, came to our institution for a dating scan at 8 weeks of gestation. The transvaginal ultrasound examination demonstrated a monochorionic diamniotic pregnancy. She and her husband were healthy, with no family history of trisomy 21 or other congenital diseases. The ultrasound examination of nuchal translucency thickness was discordant in twins at 13 weeks (twin A, NT 1.4 mm with CRL being 65 mm; twin B, NT 7.8 mm with CRL being 69 mm). At 17+ 4 weeks, twin A was normal, but ventricular septal defect and the hypoplastic left heart was detected in twin B. The deepest vertical pocket was 18 mm in twin A (oligohydramnios) and 102 mm in Twin B (polyhydramnios). The bladder in twin A was absent. Ultrasound findings indicated TTTS Stage II. Amniocentesis was performed for the two fetuses. The karyotyping results revealed 46, XX in twin A but 46,XX,+ 21,der (21;21)(q10;q10) in twin B. For twin B, the parents opted for selective fetal termination by radiofrequency ablation. The procedure was uneventful. At 40+ 5 weeks, twin A was born with a birth weight of 4120 g by vaginal delivery. CONCLUSIONS: The early detection of discordant karyotype and twin-to-twin transfusion syndrome is beneficial to the early intervention. In monozygotic twins with a discordant anomaly, the discordant karyotype should be considered.


Assuntos
Amniocentese , Síndrome de Down/genética , Transfusão Feto-Fetal/genética , Gravidez de Gêmeos/genética , Gêmeos Monozigóticos/genética , Adulto , Cromossomos Humanos Par 21/genética , Síndrome de Down/diagnóstico , Feminino , Transfusão Feto-Fetal/diagnóstico , Humanos , Recém-Nascido , Cariotipagem , Medição da Translucência Nucal , Oligo-Hidrâmnio , Gravidez , Redução de Gravidez Multifetal , Ultrassonografia Pré-Natal
2.
Nat Genet ; 53(1): 27-34, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33414551

RESUMO

Despite the important role that monozygotic twins have played in genetics research, little is known about their genomic differences. Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. Using the parents and offspring of twins, we identified pre-twinning mutations. We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages. CpG>TpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation. Our results indicate that allocations of cells during development shapes genomic differences between monozygotic twins.


Assuntos
Genoma Humano , Células Germinativas/metabolismo , Gêmeos Monozigóticos/genética , Desenvolvimento Embrionário/genética , Feminino , Frequência do Gene/genética , Humanos , Masculino , Mosaicismo , Mutação/genética , Zigoto/metabolismo
3.
Proc Natl Acad Sci U S A ; 117(35): 21546-21556, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817525

RESUMO

The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2% of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when we focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation.


Assuntos
Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Metilação de DNA , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Sintomas Prodrômicos , Gêmeos Monozigóticos/genética
4.
Adv Exp Med Biol ; 1253: 95-104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32445092

RESUMO

Genomic predisposition fails to fully explain the onset of complex diseases, which is well illustrated by the largely incomplete concordance among monozygotic twins. Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and non-coding RNA, are the link between environmental stimuli and disease onset on a permissive genetic background in autoimmune and chronic inflammatory diseases. Autoimmune diseases now include almost 100 conditions and are estimated to cumulatively affect up to 5% of the world population with a healthcare expenditure superior to cancer worldwide. Many advances in medicine have been made to treat these conditions but there are still gaps, and an innovative and efficient therapy is needed. Systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren syndrome, polymyositis, and dermatomyositis. Monozygotic twins discordant for any disease offer an ideal study design as they are matched for many factors, including genetic variation and this is a real advantage for epigenetics study. We will herein discuss the available data in the epigenetic differences leading to disease discordance in MZ twins for systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.


Assuntos
Epigênese Genética , Epigenômica/métodos , Estudos em Gêmeos como Assunto , Gêmeos Monozigóticos/genética , Doenças Autoimunes/genética , Metilação de DNA , Humanos , Inflamação/genética
5.
Eur J Endocrinol ; 182(5): 473-480, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32229696

RESUMO

Objective: Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases. Design: Prospective twin cohort study. Methods: We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto's thyroiditis, atrophic gastritis, celiac disease, Graves' disease, type 1 diabetes, vitiligo and Addison's disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data. Results: Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2-9.2) than in dizygotic twins (median HR: 2.4, range: 1.1-10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23-0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49-0.71) for Graves' disease to 0.97 (95% CI: 0.91-1.00) for Addison's disease. Conclusions: Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.


Assuntos
Autoimunidade/fisiologia , Doença de Addison/genética , Autoimunidade/genética , Doença Celíaca/genética , Estudos de Coortes , Feminino , Gastrite Atrófica/genética , Predisposição Genética para Doença/genética , Doença de Graves/genética , Humanos , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
6.
Twin Res Hum Genet ; 23(1): 33-38, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32209144

RESUMO

Life-course experiences have been postulated to program hypothalamus-pituitary-adrenal (HPA) axis activity, suggesting that HPA axis activity is, at least partially, stable over time. Yet, there is paucity of data on the long-term stability of cortisol production and metabolism. We performed a prospective follow-up study in twins recruited from a nationwide register to estimate the stability of cortisol production and metabolism over time, and the contribution of genetic and environmental factors to this stability. In total, 218 healthy mono- and dizygotic twins were included. At the ages of 9, 12 and 17 years, morning urine samples were collected for assessment (by gas chromatography-tandem mass spectrometry) of cortisol metabolites, enabling the calculation of cortisol metabolite excretion rate and cortisol metabolism activity. Our results showed a low stability for both cortisol metabolite excretion rate (with correlations <.20) and cortisol metabolism activity indices (with correlations of .25 to .46 between 9 and 12 years, -.02 to .15 between 12 and 17 years and .09 to .28 between 9 and 17 years). Because of the low stability over time, genetic and environmental contributions to this stability were difficult to assess, although it seemed to be mostly determined by genetic factors. The low stability in both cortisol production and metabolism between ages 9 and 17 years reflects the dynamic nature of the HPA axis.


Assuntos
Glucocorticoides/metabolismo , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Adolescente , Criança , Cromatografia Gasosa , Cortisona/metabolismo , Cortisona/urina , Citocromo P-450 CYP3A/metabolismo , Feminino , Seguimentos , Interação Gene-Ambiente , Estudos de Associação Genética , Glucocorticoides/urina , Humanos , Hidrocortisona/urina , Sistema Hipotálamo-Hipofisário/enzimologia , Estudos Longitudinais , Masculino , Sistema Hipófise-Suprarrenal/enzimologia , Estudos Prospectivos , Sistema de Registros , Espectrometria de Massas em Tandem , Gêmeos Dizigóticos , Gêmeos Monozigóticos/genética
7.
Twin Res Hum Genet ; 23(1): 51-54, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32209150

RESUMO

Dichorionic diamniotic (DCDA) twin pregnancies after single blastocyst embryo transfer have been reported recently, although a blastocyst ovum is generally believed to divide into monochorionic twin pregnancy. We investigated the incidence of DCDA twin pregnancy after single blastocyst embryo transfer and their zygosity. This prospective cohort study included 655 consecutive twin pregnancies that were managed from 2006 to 2014 at our institution. Chorionicity and amnionicity were determined using first-trimester ultrasonography and/or placental pathology. Zygosity was analyzed if the cases were DCDA twins after single blastocyst embryo transfer. Among 655 twin pregnancies, there were 348 DCDA cases, 295 monochorionic diamniotic (MCDA) cases and 12 monochorionic monoamniotic cases. Single blastocyst embryo transfer was performed in 43 cases. Six out of the 43 (14%) cases involved DCDA twin pregnancies and the other 37 cases involved MCDA twin pregnancies. Three DCDA twins born after single blastocyst embryo transfer, wherein frozen embryo transfer (FET) was performed in the natural cycle, were dizygotic, and the other three cases, wherein FET with hormone replacement therapy was performed, were monozygotic. DCDA twin pregnancy occurred in 14% (7% for monozygotic and 7% for dizygotic) of twin pregnancies after single blastocyst embryo transfer cases.


Assuntos
Âmnio/diagnóstico por imagem , Córion/diagnóstico por imagem , Gêmeos Monozigóticos/estatística & dados numéricos , Adulto , Âmnio/crescimento & desenvolvimento , Blastocisto , Córion/crescimento & desenvolvimento , Estudos de Coortes , Transferência Embrionária , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Gêmeos Dizigóticos/genética , Gêmeos Dizigóticos/estatística & dados numéricos , Gêmeos Monozigóticos/genética , Ultrassonografia Pré-Natal
8.
Taiwan J Obstet Gynecol ; 59(1): 123-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039779

RESUMO

OBJECTIVE: We present the prenatal diagnosis of a class II 1q21.1 microdeletion in monozygotic (MZ) twins with discordant phenotypes. CASE REPORT: A monochorionic diamniotic twin pair presented with discordant ultrasound anomalies; twin A had cardiovascular abnormalities, while twin B did not. No specific complications were noted in the twins during pregnancy. A single nucleotide polymorphism array revealed an identical class II 1q21.1 microdeletion inherited from a phenotypically normal mother and identified the twins as MZ. The deleted region encompassed both the proximal 1q21.1 thrombocytopenia absent radius syndrome region and the distal 1q21.1 recurrent microdeletion region. No other rare copy number variants (CNVs) were identified, and concordance was observed in the CNVs between the twins. CONCLUSION: Discordant cardiovascular abnormalities may occur in MZ twins carrying the same class II 1q21.1 microdeletion. Further studies involving discordant MZ twins are needed to determine the modifying factors of the phenotypic heterogeneity of the microdeletion.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Cardiovasculares/diagnóstico , Doenças em Gêmeos/diagnóstico , Megalencefalia/diagnóstico , Diagnóstico Pré-Natal/métodos , Gêmeos Monozigóticos/genética , Anormalidades Múltiplas/genética , Adulto , Anormalidades Cardiovasculares/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Variações do Número de Cópias de DNA , Doenças em Gêmeos/genética , Feminino , Humanos , Megalencefalia/genética , Fenótipo , Gravidez , Gravidez de Gêmeos/genética
9.
Behav Genet ; 50(2): 127-138, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32040643

RESUMO

The univariate bootstrap is a relatively recently developed version of the bootstrap (Lee and Rodgers in Psychol Methods 3(1): 91, 1998). DeFries-Fulker (DF) analysis is a regression model used to estimate parameters in behavioral genetic models (DeFries and Fulker in Behav Genet 15(5): 467-473, 1985). It is appealing for its simplicity; however, it violates certain regression assumptions such as homogeneity of variance and independence of errors that make calculation of standard errors and confidence intervals problematic. Methods have been developed to account for these issues (Kohler and Rodgers in Behav Genet 31(2): 179-191, 2001), however the univariate bootstrap represents a unique means of doing so that is presaged by suggestions from previous DF research (e.g., Cherny et al. in Behav Genet 22(2): 153-162, 1992). In the present study we use simulations to examine the performance of the univariate bootstrap in the context of DF analysis. We compare a number of possible bootstrap schemes as well as more traditional confidence interval methods. We follow up with an empirical demonstration, applying results of the simulation to models estimated to investigate changes in body mass index in adults from the National Longitudinal Survey of Youth 1979 data.


Assuntos
Interpretação Estatística de Dados , Genética Comportamental/métodos , Modelos Estatísticos , Adolescente , Adulto , Índice de Massa Corporal , Peso Corporal/genética , Intervalos de Confiança , Feminino , Humanos , Estudos Longitudinais , Masculino , Modelos Genéticos , Fenótipo , Análise de Regressão , Meio Social , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto Jovem
10.
Brain ; 143(3): 920-931, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32025699

RESUMO

A variety of cellular processes, including vesicle clustering in the presynaptic compartment, are impaired in Parkinson's disease and have been closely associated with α-synuclein oligomerization. Emerging evidence proves the existence of α-synuclein-related pathology in the peripheral nervous system, even though the presence of α-synuclein oligomers in situ in living patients remains poorly investigated. In this case-control study, we show previously undetected α-synuclein oligomers within synaptic terminals of autonomic fibres in skin biopsies by means of the proximity ligation assay and propose a procedure for their quantification (proximity ligation assay score). Our study revealed a significant increase in α-synuclein oligomers in consecutive patients with Parkinson's disease compared to consecutive healthy controls (P < 0.001). Proximity ligation assay score (threshold value > 96 using receiver operating characteristic) was found to have good sensitivity, specificity and positive predictive value (82%, 86% and 89%, respectively). Furthermore, to disclose the role of putative genetic predisposition in Parkinson's disease aetiology, we evaluated the differential accumulation of oligomers in a unique cohort of 19 monozygotic twins discordant for Parkinson's disease. The significant difference between patients and healthy subjects was confirmed in twins. Intriguingly, although no difference in median values was detected between consecutive healthy controls and healthy twins, the prevalence of healthy subjects positive for proximity ligation assay score was significantly greater in twins than in the consecutive cohort (47% versus 14%, P = 0.019). This suggests that genetic predisposition is important, but not sufficient, in the aetiology of the disease and strengthens the contribution of environmental factors. In conclusion, our data provide evidence that α-synuclein oligomers accumulate within synaptic terminals of autonomic fibres of the skin in Parkinson's disease for the first time. This finding endorses the hypothesis that α-synuclein oligomers could be used as a reliable diagnostic biomarker for Parkinson's disease. It also offers novel insights into the physiological and pathological roles of α-synuclein in the peripheral nervous system.


Assuntos
Imunoensaio/métodos , Doença de Parkinson/metabolismo , Pele/metabolismo , Sinucleínas/metabolismo , Gêmeos Monozigóticos/genética , Sistema Nervoso Autônomo/metabolismo , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Terminações Pré-Sinápticas/metabolismo
11.
Twin Res Hum Genet ; 23(1): 39-44, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32083524

RESUMO

Type 2 diabetes, which is caused by both genetic and environmental factors, may be diagnosed using the oral glucose tolerance test (OGTT). Recent studies demonstrated specific patterns in glucose curves during OGTT associated with cardiometabolic risk profiles. As the relative contribution of genetic and environmental influences on glucose curve patterns is unknown, we aimed to investigate the heritability of these patterns. We studied twins from the Danish GEMINAKAR cohort aged 18-67 years and free from diabetes at baseline during 1997-2000; glucose concentrations were measured three times during a 2-h OGTT. Heterogeneity of the glucose response during OGTT was examined with latent class mixed-effects models, evaluating goodness of fit by Bayes information criterion. The genetic influence on curve patterns was estimated using quantitative genetic modeling based on linear structural equations. Overall, 1455 twins (41% monozygotic) had valid glucose concentrations measured from the OGTT, and four latent classes with different glucose response patterns were identified. Statistical modeling demonstrated genetic influence for belonging to a specific class or not, with heritability estimated to be between 45% and 67%. During ∼12 years of follow-up, the four classes were each associated with different incidence of type 2 diabetes. Hence, glucose response curve patterns associated with type 2 diabetes risk appear to be moderately to highly heritable.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Teste de Tolerância a Glucose/estatística & dados numéricos , Adolescente , Adulto , Idoso , Teorema de Bayes , Estudos de Coortes , Dinamarca , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Seguimentos , Variação Genética , Teste de Tolerância a Glucose/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
12.
Psychiatr Genet ; 30(2): 60-63, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32106127

RESUMO

Whole-exome sequencing (WES) studies have shown that de-novo variants contribute to the genetic etiology of schizophrenia. WES studies of families with a monozygotic twin pair concordant or discordant for a disease may be fruitful for identifying de-novo pathogenic variants. Here, we performed WES in six individuals from one family (affected monozygotic twins, their unaffected parents, and two siblings) and identified three de-novo missense variants (CPT2 Ala283Thr, CPSF3 Val584Ile, and RNF148 Val210Ile) in the monozygotic twin pair concordant for schizophrenia. These three missense variants were not found in 1760 patients with schizophrenia or schizoaffective disorder or 1508 healthy controls. Our data do not support the role of the three missense variants in conferring risk for schizophrenia.


Assuntos
Transtornos Psicóticos/genética , Esquizofrenia/genética , Adulto , Carnitina O-Palmitoiltransferase/genética , Estudos de Casos e Controles , Fator de Especificidade de Clivagem e Poliadenilação/genética , Variações do Número de Cópias de DNA/genética , Exoma , Feminino , Seguimentos , Predisposição Genética para Doença/genética , Humanos , Masculino , Linhagem , Análise de Sequência de DNA , Irmãos , Gêmeos Monozigóticos/genética , Ubiquitina-Proteína Ligases/genética , Sequenciamento Completo do Exoma/métodos
13.
Gene ; 738: 144461, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32057927

RESUMO

Down syndrome is one of the most common chromosomal disorders and yet our understanding about the dysregulated genes in this disease is limited. Through this case study, we investigated the gene expression profile of primary amniotic fluid mesenchymal stem cells (AFMSCs) isolated from the amniotic sac of monozygotic twins discordant for trisomy 21 with one fetal hydrops at 17 weeks of gestation. AFMSCs were cultured to analyze the gene expression profiles for the human transcriptome array. Gene ontology was used to evaluate dysregulated gene functions. Total 25,799 genes were identified such that 65 were up-regulated (0.25%) and 111 were down-regulated (0.43%) with a log2 fold change trisomy 21/euploidy (log2 [FC]) > 1, p < 0.01). 16 genes were selected and verified by qRT-PCR, which showed compatible result with transcriptome array. At the chromosome level, chromosome 21 was found to carry the highest percentage of up-regulated genes (2.13%, 7/329 genes) with the highest mean log2 [FC] (0.23, p < 10-5), particularly on 21q22.3. There were eight segments with significant mean log2 [FC] on chromosomes 1, 6, 11, and 21 for upregulation, and on chromosomes 16, 17, and 19 for downregulation, indicating a pattern of dysregulated genes clustering in domains along the genome. Gene ontology showed the identified genes associated with extracellular matrix organization (11 genes, p = 5.1 × 10-6) and central nervous system development (8 genes, p = 6.0 × 10-5). Using transcriptome analysis of the AFMSCs of monozygotic twins discordant for trisomy 21, we report the dysregulated genes involved in Down syndrome, their predominance on chromosome 21, and the cluster pattern on the whole genome.


Assuntos
Síndrome de Down/genética , Perfilação da Expressão Gênica/métodos , Análise em Microsséries/métodos , Líquido Amniótico , Transtornos Cromossômicos/genética , Doenças em Gêmeos/genética , Feminino , Ontologia Genética , Genoma , Genótipo , Humanos , Células-Tronco Mesenquimais/fisiologia , Fenótipo , Gravidez , Transcriptoma/genética , Trissomia/genética , Gêmeos Monozigóticos/genética
14.
Mol Genet Metab ; 129(3): 236-242, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31917109

RESUMO

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.


Assuntos
Doenças em Gêmeos/genética , Complexo I de Transporte de Elétrons/metabolismo , Leucoencefalopatias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Tálamo/diagnóstico por imagem , Linhagem Celular , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Doenças em Gêmeos/diagnóstico por imagem , Doenças em Gêmeos/metabolismo , Doenças em Gêmeos/fisiopatologia , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Cápsula Externa/diagnóstico por imagem , Cápsula Externa/patologia , Olho/fisiopatologia , Fibroblastos/metabolismo , Humanos , Lactente , Ácido Láctico/metabolismo , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/metabolismo , Leucoencefalopatias/fisiopatologia , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mitocôndrias/genética , Proteínas Mitocondriais/metabolismo , Mutação , NADH Desidrogenase/metabolismo , Gêmeos Monozigóticos/genética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Sequenciamento Completo do Exoma
15.
Twin Res Hum Genet ; 23(1): 8-15, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31983355

RESUMO

In 1984, Hrubec and Robinette published what was arguably the first review of the role of twins in medical research. The authors acknowledged a growing distinction between two categories of twin studies: those aimed at assessing genetic contributions to disease and those aimed at assessing environmental contributions while controlling for genetic variation. They concluded with a brief section on recently founded twin registries that had begun to provide unprecedented access to twins for medical research. Here we offer an overview of the twin research that, in our estimation, best represents the field has progress since 1984. We start by summarizing what we know about twinning. We then focus on the value of twin study designs to differentiate between genetic and environmental influences on health and on emerging applications of twins in multiple areas of medical research. We finish by describing how twin registries and networks are accelerating twin research worldwide.


Assuntos
Doenças em Gêmeos/genética , Interação Gene-Ambiente , Estudos em Gêmeos como Assunto , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Pesquisa Biomédica/métodos , Doenças em Gêmeos/congênito , Doenças em Gêmeos/embriologia , Epigênese Genética/fisiologia , Feminino , Humanos , Masculino , Microbiota/genética , Sistema de Registros , Células-Tronco/metabolismo , Células-Tronco/patologia
16.
Psychiatry Res ; 286: 112548, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31495512

RESUMO

Posttraumatic stress disorder (PTSD) and insomnia are comorbid clinical conditions that are thought to result from genetic and environmental effects. Though studies have established the heritability of these disorders independently, no study to date has examined the genetic contributions to the relation between insomnia and PTSD symptoms (PTSS). The present study assessed this gap in the literature using a behavioral genetics approach to symptom dimensions. The sample consisted of 242 twin pairs who endorsed lifetime trauma exposure. Insomnia symptoms were assessed with the Women's Health Initiative Survey, and intrusion and avoidance PTSS were assessed with the Impact of Events Scale. Structural equation modeling was then employed to test the relative contributions of genetic, shared environmental, and nonshared environmental components to the relations between insomnia symptoms and intrusions and avoidance. Results indicated a significant association between insomnia symptoms and intrusions (r = 0.33, p < 0.01) and insomnia symptoms and avoidance (r = 0.20, p < 0.01), and 36-44% of phenotypic variance was accounted for by genetic contributions. These findings highlight a significant role for genetic factors in the mechanisms underlying the comorbidity between insomnia and PTSS. The implications for current etiological models of PTSD and insomnia are discussed.


Assuntos
Doenças em Gêmeos/etiologia , Doenças em Gêmeos/genética , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/genética , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/genética , Gêmeos/genética , Adulto , Idoso , Comorbidade , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Washington/epidemiologia
17.
Eur J Med Genet ; 63(3): 103737, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31419599

RESUMO

Mutations in KDM5C (lysine (K)-specific demethylase 5C) were causally associated with up to 3% of X-linked intellectual disability (ID) in males. By exome and Sanger sequencing, a novel frameshift KDM5C variant, predicted to eliminate the JmjC catalytic domain from the protein, was identified in two monozygotic twins and their older brother, which was inherited from their clinically normal mother, who had completely skewed X-inactivation. DNA methylation (DNAm) data were evaluated using the Illumina 450 K Methylation Beadchip arrays. Comparison of methylation levels between the three patients and male controls identified 399 differentially methylated CpG sites, which were enriched among those CpG sites modulated during brain development. Most of them were hypomethylated (72%), and located mainly in shores, whereas the hypermethylated CpGs were more represented in open sea regions. The DNAm changes did not differ between the monozygotic twins nor between them and their older sibling, all presenting a global hypomethylation, similar to other studies that associated DNA methylation changes to different KDM5C mutations. The 38 differentially methylated regions (DMRs) were enriched for H3K4me3 marks identified in developing brains. The remarkable similarity between the methylation changes in the monozygotic twins and their older brother is indicative that these epigenetic changes were mostly driven by the KDM5C mutation.


Assuntos
Encéfalo/metabolismo , Doenças em Gêmeos/genética , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Gêmeos Monozigóticos/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Criança , Ilhas de CpG , Metilação de DNA , Doenças em Gêmeos/fisiopatologia , Epigênese Genética , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X/genética , Histonas/genética , Histonas/metabolismo , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Análise em Microsséries , Irmãos , Sequenciamento Completo do Exoma
18.
Eur J Med Genet ; 63(3): 103739, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31421289

RESUMO

The chromatin remodeling AT-Rich interaction domain containing 1B protein (ARID1B) also known as BAF-associated factor, 250-KD, B (BAF250B) codified by the ARID1B gene (MIM#614556), is a small subunit of the mammalian SWI/SNF or BAF complex, an ATP-dependent protein machinery which is able to activate or repress gene transcription, allowing protein access to histones through DNA relaxed conformation. ARID1B gene mutations have been associated with two hereditary syndromic conditions, namely Coffin-Siris (CSS, MIM#135900) and Nicolaides-Baraitser syndromes (NCBRS, MIM#601358), characterized by neurodevelopment delay, craniofacial dysmorphisms and skeletal anomalies. Furthermore, intellectual impairment and central nervous system (CNS) alterations, comprising abnormal corpus callosum, have been associated with mutations in this gene. Moreover, ARID1B anomalies resulted to be involved in neoplastic events and Hirschprung disease. Here we report on two monozygotic male twins, displaying clinical appearance strikingly resembling NCBRS and CSS phenotype, who resulted carriers of a novel 6q25.3 microdeletion, encompassing only part of the ARID1B gene. The deleted segment was not inherited from the only parent tested and afflicted the first exons of the gene, coding for protein disordered region. We also provide, for the first time, a review of previously published ARID1B mutated patients with NCBRS and CSS phenotype and a computer-assisted dysmorphology analysis of NCBRS and ARID1B related CSS individuals, through the Face2Gene suite, confirming the existence of highly overlapping facial gestalt of both conditions. The present findings indicate that ARID1B could be considered a contributing gene not only in CSS but also in NCBRS phenotype, although the main gene related to this latter condition is the SMARCA2 gene (MIM#600014), another component of the BAF complex. So, ARID1B study should be considered in such individuals.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Hipotricose/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fatores de Transcrição/genética , Gêmeos Monozigóticos/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Face/diagnóstico por imagem , Face/patologia , Face/fisiopatologia , Facies , Deformidades Congênitas do Pé/diagnóstico por imagem , Deformidades Congênitas do Pé/patologia , Deformidades Congênitas do Pé/fisiopatologia , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/patologia , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Hipotricose/diagnóstico por imagem , Hipotricose/patologia , Hipotricose/fisiopatologia , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Micrognatismo/diagnóstico por imagem , Micrognatismo/patologia , Micrognatismo/fisiopatologia , Mutação de Sentido Incorreto , Pescoço/diagnóstico por imagem , Pescoço/patologia , Pescoço/fisiopatologia , Fenótipo , Processamento de RNA , Deleção de Sequência
19.
Blood ; 135(4): 261-268, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31697811

RESUMO

Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is defined by mutations in myeloid cancer-associated genes with a variant allele frequency of at least 2%. Recent studies have suggested a possible genetic predisposition to CH. To further explore this phenomenon, we conducted a population-based study of 594 twins from 299 pairs aged 73 to 94 years, all with >20 years' follow-up. We sequenced DNA from peripheral blood with a customized 21-gene panel at a median coverage of 6179X. The casewise concordance rates for mutations were calculated to assess genetic predisposition. Mutations were identified in 214 (36%) of the twins. Whereas 20 twin pairs had mutations within the same genes, the exact same mutation was only observed in 2 twin pairs. No significant difference in casewise concordance between monozygotic and dizygotic twins was found for any specific gene, subgroup, or CHIP mutations overall, and no significant heritability could be detected. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the association of having CH when controlling for familial factors. A total of 127 twin pairs were discordant for carrying a mutation, and in 61 (48%) cases, the affected twin died first (P = .72). Overall, we did not find a genetic predisposition to CHIP mutations in this twin study. The previously described negative association of CHIP mutations on survival could not be confirmed in a direct comparison among twin pairs that were discordant for CHIP mutations.


Assuntos
Hematopoese , Leucemia Mieloide/genética , Gêmeos/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doenças em Gêmeos/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide/mortalidade , Masculino , Mutação , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
20.
Blood ; 135(4): 269-273, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31697828

RESUMO

Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero.


Assuntos
Hematopoese , Leucemia/genética , Mutação , Gêmeos/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doenças em Gêmeos/genética , Feminino , Humanos , Masculino , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
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