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1.
J Stroke Cerebrovasc Dis ; 30(9): 105997, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303089

RESUMO

OBJECTIVES: To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease. MATERIALS AND METHODS: A total of 6 individuals, of whom 3 are severely affected, from the family were clinically and radiologically evaluated. SNP genotyping was performed in multiple members to demonstrate genome-wide runs-of-homozygosity. Coding variants in the most likely candidate gene, HTRA1 were explored by Sanger sequencing. Published HTRA1-related phenotypes were extensively reviewed to explore the effect of number of affected alleles on phenotypic expression. RESULTS: Genome-wide homozygosity mapping identified a 3.2 Mbp stretch on chromosome 10q26.3 where HTRA1 gene is located. HTRA1 sequencing revealed an evolutionarily conserved novel homozygous c.824C>T (p.Pro275Leu) mutation, affecting the serine protease domain of HtrA1. Early-onset of cognitive and motor deterioration in homozygotes are in consensus with CARASIL. However, there was a clear phenotypic variability between homozygotes which includes alopecia, a suggested hallmark of CARASIL. All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation. CONCLUSION: Here, we clearly demonstrate that CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities thorough the evaluation of the largest collection of homozygotes and heterozygotes segregating in a family. Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms.


Assuntos
Alopecia/genética , CADASIL/genética , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Adulto , Idade de Início , Alopecia/diagnóstico , Alopecia/fisiopatologia , CADASIL/diagnóstico , CADASIL/fisiopatologia , Infarto Cerebral/diagnóstico , Infarto Cerebral/fisiopatologia , Consanguinidade , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Índice de Gravidade de Doença , Doenças da Coluna Vertebral/diagnóstico , Doenças da Coluna Vertebral/fisiopatologia
2.
Vasc Health Risk Manag ; 17: 415-419, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34321884

RESUMO

The "Lebanese allele" {LDLR c.2043 C>A (p.cys681X)} is a nonsense mutation in the low-density lipoprotein receptor (LDLR) gene that results in a truncated non-functioning LDLR protein. We report two sisters of Lebanese descent who presented with familial hypercholesterolemia (FH) and were both heterozygous for the Lebanese allele, but had very distinct LDL-C levels and clinical phenotypes. Whereas one of the sisters had LDL-C in the expected range of Heterozygous FH (HeFH) with the Lebanese allele (LDL-C of 292 mg/dl), the other sister had a more severe LDL-C phenotype in the Homozygous FH (HoFH) range (LDL-C of 520 mg/dl) along with manifest atherosclerosis. Surprisingly, she did not demonstrate a compound heterozygote or double heterozygote status. We discuss different mechanisms that are purported to play a role in modifying the phenotype of FH, including different variants and polygenic modifiers. HeFH patients with the Lebanese allele can have a wide spectrum of LDL-C levels that range from the typical heterozygous to homozygous phenotypes.


Assuntos
LDL-Colesterol/sangue , Códon sem Sentido , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , Irmãos , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Pessoa de Meia-Idade , Linhagem , Fenótipo , Índice de Gravidade de Doença
3.
Lancet Oncol ; 22(7): 1014-1022, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34111421

RESUMO

BACKGROUND: Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. METHODS: In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. FINDINGS: 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p<0·0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A>T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. INTERPRETATION: Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. FUNDING: National Health and Medical Research Council, Australia.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Interação Gene-Ambiente , Características de Residência , Adulto , Fatores Etários , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais
4.
Virchows Arch ; 479(1): 221-226, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34100114

RESUMO

Salivary gland cancers (SGCs) are rare malignancies with highly heterogeneous histological features. Patients affected with SGCs are at increased risk of secondary malignancies, including breast cancer (BC). Previous studies enlightened a possible link between SGCs and hereditary predisposition to BC. Here, we searched for SGC-affected patients in 1796 high-risk BC families recruited at the Genetic Unit of the Istituto Nazionale dei Tumori of Milan, 516 of which carried pathogenic variants in BRCA1 and/or BRCA2, the main genetic risk factors for BC. We detected five families with an individual affected with SGC, including two male patients, one carrying a constitutional mutation in BRCA1 and the other in BRCA2. Loss of heterozygosity of BRCA wild-type alleles was assessed in the patients' tumour DNA. We conclude that our observations support the hypothesis that genetic factors associated with BC susceptibility might play a role also in at least a subset of SGCs.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Mutação , Neoplasias das Glândulas Salivares/genética , Adulto , Bases de Dados Factuais , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Itália , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Linhagem
5.
J Stroke Cerebrovasc Dis ; 30(8): 105674, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34119749

RESUMO

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by the Notch3 gene mutation, has its unique clinical and imaging characteristics. Here we present a Chinese family with a novel mutation on exon 10 of Notch3 gene. METHODS: Clinical and MRI data of the three patients in the family during the 7-year follow-up were collected. The CADASIL Scale Score was calculated to evaluate the disease risk of the three patients at their first admission or clinic visit. Five family members underwent genetic test. RESULTS: Genetic test confirmed the diagnosis of CADASIL in this family. A novel mutation of p.C533S on exon 10 of Notch3 gene was detected. The CADASIL score of the proband and her sister was both 17 and that of her brother was 14. CONCLUSIONS: Our report not only expands the mutation spectrum of Notch3 gene in CADASIL, but also shows the distinct heterogeneity of CADASIL patients in the same family with the same mutation.


Assuntos
CADASIL/genética , Mutação de Sentido Incorreto , Receptor Notch3/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , CADASIL/diagnóstico , CADASIL/etnologia , China , Análise Mutacional de DNA , Éxons , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
6.
Nat Commun ; 12(1): 3714, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140513

RESUMO

The mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr model and genome-wide differential DNA methylation in the germline of Mtrr mutant maternal grandfathers. We observe that, while epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional changes that correlate with germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos for at least three wildtype generations in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Metilação de DNA , Ferredoxina-NADP Redutase/genética , Ácido Fólico/metabolismo , Células Germinativas/metabolismo , Chaperonas de Histonas/metabolismo , Padrões de Herança/genética , Herança Materna/genética , Fatores de Transcrição/metabolismo , Animais , Biomarcadores/metabolismo , Proteínas de Ciclo Celular/genética , Embrião de Mamíferos/metabolismo , Epigênese Genética , Epigenômica , Feminino , Ferredoxina-NADP Redutase/metabolismo , Hereditariedade , Chaperonas de Histonas/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Espermatozoides/metabolismo , Fatores de Transcrição/genética , Trofoblastos/metabolismo , Sequenciamento Completo do Genoma
7.
Rev Med Liege ; 76(5-6): 327-336, 2021 May.
Artigo em Francês | MEDLINE | ID: mdl-34080359

RESUMO

A personal or family history of cancer has now become the primary cause of genetic consultations. In recent years, various genes have been identified that are associated with a more or less marked genetic predisposition to the development of cancers. The syndrome associated with the hereditary risk of breast and ovarian cancer and the Lynch syndrome are the most frequent ones, but there are many other, much less common, situations associated with familial cancer risk. In most cases, there are clear recommendations regarding the indications for genetic testing and the follow-up of patients identified as having a predisposition to cancer. At the CHU of Liège, we currently perform more than 1.400 oncogenetic consultations per year and we maintain a positivity rate of genetic tests performed in this indication higher than 10%. In this way, we allow a multidisciplinary care of patients with a high oncological risk and participate in a prevention and surveillance activity. We also pay increasing attention to the hereditary risk associated with pediatric cancers and to patients with multiple cancers, especially when these develop at an early age. Finally, the oncogenetic consultation must consider the psychological, ethical and legal aspects of a diagnosis that involves the patient and his or her future, but also the whole family.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Hereditariedade , Neoplasias Ovarianas , Criança , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos
8.
Br J Hist Sci ; 54(2): 213-231, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34011428

RESUMO

Mendelian Inheritance in Man (MIM), a computerized catalogue of human genetic disorders authored and maintained by cardiologist and medical genetics pioneer Victor A. McKusick, played a major part in demarcating between a novel biomedical science and the eugenic projects of racial betterment which existed prior to its emergence. Nonetheless, it built upon prior efforts to systematize genetic knowledge tied to individuals and institutions invested in eugenics. By unpacking the process of digitizing a homespun cataloguing project and charting its development into an online database, this article aims to illuminate how the institution-building efforts of one individual created an 'information order' for accessing genetic information that tacitly shaped the norms and priorities of the field toward the pursuit of specific genes associated with discernible genetic disorders. This was not by design, but rather arose through negotiation with the catalogue's users; it accommodated further changes as biomedical research displaced the Mendelian paradigm. While great effort was expended toward making sequence data available to investigators during the Human Genome Project, MIM was largely taken for granted as a 'legacy system', McKusick's own labour of love. Drawing on recent histories of biomedical data, the article suggests that the bibliographical work of curation and translation is a central feature of value production in the life sciences meriting attention in its own right.


Assuntos
Bases de Dados Genéticas/história , Genética Médica/história , Hereditariedade , Editoração/história , História do Século XX , História do Século XXI , Humanos
9.
Poult Sci ; 100(7): 101164, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34058565

RESUMO

Epigenetics is defined as the study of changes in gene function that are mitotically or meiotically heritable and do not lead to a change in DNA sequence. Epigenetic modifications are important mechanisms that fine tune the expression of genes in response to extracellular signals and environmental changes. In vertebrates, crucial epigenetic reprogramming events occur during early embryogenesis and germ cell development. Chicken embryo, which develops external to the mother's body, can be easily manipulated in vivo and in vitro, and hence, it is an excellent model for performing epigenetic studies. Environmental factors such as temperature can affect the development of an embryo into the phenotype of an adult. A better understanding of the environmental impact on embryo development can be achieved by analyzing the direct effects of epigenetic modifications as well as their molecular background and their intergenerational and transgenerational inheritance. In this overview, the current possibility of epigenetic changes during chicken embryonic development and their effects on long-term postembryonic development are discussed.


Assuntos
Galinhas , Hereditariedade , Animais , Embrião de Galinha , Metilação de DNA , Desenvolvimento Embrionário , Epigênese Genética , Fenótipo
10.
Front Immunol ; 12: 625591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868243

RESUMO

Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive (AR) immune disorder that has usually been associated to missense, nonsense or indels mutations in the LYST gene. In this study, we describe for the first time the case of a CHS patient carrying a homozygous mutation in the LYST gene inherited as a result of a partial uniparental isodisomy (UPiD) of maternal origin. Sanger sequencing of the LYST cDNA and single nucleotide polymorphism (SNP)-arrays were performed to identify the causative mutation and to explain the molecular mechanism of inheritance, respectively. Partial-UPiD leads to a copy neutral loss of heterozygosity (CN-LOH) of the telomeric region of chromosome 1 (1q41q44), unmasking the potential effect of the mutation detected. The mutation (c.8380dupT) is an insertion located in exon 32 of the LYST gene resulting in a premature stop codon and leading to the loss of all the conserved domains at the C-terminal of the LYST protein. This would account for the severe phenotype observed. We also reviewed the only two previously reported cases of CHS as a result of a uniparental disomy. In this study, we show that the combination of different strategies, including the use of SNP-arrays, is pivotal to fine-tune the diagnosis of rare AR disorders, such as CHS. Moreover, this case highlights the relevance of uniparental disomy as a potential mechanism of CHS expression in non-consanguineous families.


Assuntos
Síndrome de Chediak-Higashi/genética , Mutação , Dissomia Uniparental , Proteínas de Transporte Vesicular/genética , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/terapia , Pré-Escolar , Feminino , Predisposição Genética para Doença , Hereditariedade , Homozigoto , Humanos , Perda de Heterozigosidade , Técnicas de Diagnóstico Molecular , Mães , Linhagem , Fenótipo , Índice de Gravidade de Doença
11.
J Stroke Cerebrovasc Dis ; 30(6): 105744, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33813081

RESUMO

BACKGROUND AND OBJECTIVES: Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by pathogenic variants in the ABCC6 gene. The phenotypic spectrum of PXE is highly variable and includes principally three major features: skin lesions, eye and vascular manifestations, while brain manifestations are less common. To date about 400 different PXE associated variants in ABCC6 gene are described without any evident genotype-phenotype correlation. Herein, we report the clinical and molecular findings of a large PXE family with clinical and genetic intra-familial variability with significant cerebrovascular involvement. METHODS: The analysis of the ABCC6 gene was performed in the proband and her familiars for the definition of genetic background. Then, in order to determine why some affected individuals had more prominent brain involvement, we investigated classic thrombophilic gene variants. RESULTS: Molecular findings disclosed two different ABCC6 mutations, i.e., the recurrent p.(Arg518Gln) and the novel p.(Val1285Met) missense substitution responsible of a pseudo-dominant inheritance. The study of thrombophilic gene variants revealed the presence of 4G/4G SERPINE1 genotype in the proband and in her father, which both developed ischemic stroke. The proband carried also the C677T variant the MTHFR gene. CONCLUSION: We argue, for the first time, that the 4G/4G SERPINE1 genotype could represent an additional risk factor in PXE for developing ischemic stroke, which adds up to the already known predisposing conditions. Therapeutic implications are discussed, we also advise that PXE patients should be adequately screened for cerebral vasculopathy, even more if familial history is suggestive of brain complications.


Assuntos
Heterogeneidade Genética , AVC Isquêmico/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Pseudoxantoma Elástico/genética , Trombofilia/genética , Adulto , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico , Masculino , Linhagem , Pseudoxantoma Elástico/complicações , Pseudoxantoma Elástico/diagnóstico , Medição de Risco , Fatores de Risco , Trombofilia/sangue , Trombofilia/complicações , Trombofilia/diagnóstico
12.
Science ; 372(6537)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33795431

RESUMO

Culture can be defined as all that is learned from others and is repeatedly transmitted in this way, forming traditions that may be inherited by successive generations. This cultural form of inheritance was once thought specific to humans, but research over the past 70 years has instead revealed it to be widespread in nature, permeating the lives of a diversity of animals, including all major classes of vertebrates. Recent studies suggest that culture's reach may extend also to invertebrates-notably, insects. In the present century, the reach of animal culture has been found to extend across many different behavioral domains and to rest on a suite of social learning processes facilitated by a variety of selective biases that enhance the efficiency and adaptiveness of learning. Far-reaching implications, for disciplines from evolutionary biology to anthropology and conservation policies, are increasingly being explored.


Assuntos
Comportamento Animal , Invertebrados , Comportamento Social , Vertebrados , Animais , Evolução Biológica , Mimetismo Biológico , Comportamento Consumatório , Evolução Cultural , Cultura , Hereditariedade , Humanos , Invertebrados/genética , Invertebrados/fisiologia , Aprendizagem , Comportamento de Utilização de Ferramentas , Vertebrados/genética , Vertebrados/fisiologia , Vocalização Animal
13.
Front Immunol ; 12: 629457, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679772

RESUMO

Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.


Assuntos
Agamaglobulinemia/genética , Haploinsuficiência , Doenças Hereditárias Autoinflamatórias/genética , Mutação com Perda de Função , Lúpus Eritematoso Sistêmico/genética , Linfadenopatia/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Adolescente , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/imunologia , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença , Glucocorticoides/uso terapêutico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/imunologia , Hereditariedade , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Linfadenopatia/diagnóstico , Linfadenopatia/tratamento farmacológico , Linfadenopatia/imunologia , Linhagem , Fenótipo , Valor Preditivo dos Testes , Resultado do Tratamento
14.
Fertil Steril ; 115(6): 1521-1532, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33745725

RESUMO

OBJECTIVE: To validate and apply a strategy permitting parallel preimplantation genetic testing (PGT) for mitochondrial DNA (mtDNA) disease and aneuploidy (PGT-A). DESIGN: Preclinical test validation and case reports. SETTING: Fertility centers. Diagnostics laboratory. PATIENTS: Four patients at risk of transmitting mtDNA disease caused by m.8993T>G (Patients A and B), m.10191T>G (Patient C), and m.3243A>G (Patient D). Patients A, B, and C had affected children. Patients A and D displayed somatic heteroplasmy for mtDNA mutations. INTERVENTIONS: Embryo biopsy, genetic testing, and uterine transfer of embryos predicted to be euploid and mutation-free. MAIN OUTCOME MEASURES: Test accuracy, treatment outcomes, and mutation segregation. RESULTS: Accuracy of mtDNA mutation quantification was confirmed. The test was compatible with PGT-A, and half of the embryos tested were shown to be aneuploid (16/33). Mutations were detected in approximately 40% of embryo biopsies from Patients A and D (10/24) but in none from Patients B and C (n = 29). Patients B and C had healthy children following PGT and natural conception, respectively. The m.8993T>G mutation displayed skewed segregation, whereas m.3243A>G mutation levels were relatively low and potentially impacted embryo development. CONCLUSIONS: Considering the high aneuploidy rate, strategies providing a combination of PGT for mtDNA disease and aneuploidy may be advantageous compared with approaches that consider only mtDNA. Heteroplasmic women had a higher incidence of affected embryos than those with undetectable somatic mutant mtDNA but were still able to produce mutation-free embryos. While not conclusive, the results are consistent with the existence of mutation-specific segregation mechanisms occurring during oogenesis and possibly embryogenesis.


Assuntos
Aneuploidia , Blastocisto/patologia , Análise Mutacional de DNA , DNA Mitocondrial/genética , Fertilização In Vitro , Doença de Leigh/diagnóstico , Mutação , Diagnóstico Pré-Implantação , Adulto , Feminino , Predisposição Genética para Doença , Hereditariedade , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doença de Leigh/genética , Doença de Leigh/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Valor Preditivo dos Testes , Gravidez , Reprodutibilidade dos Testes
15.
Commun Biol ; 4(1): 158, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542458

RESUMO

Deficiency for telomerase results in transgenerational shortening of telomeres. However, telomeres have no known role in transgenerational epigenetic inheritance. C. elegans Protection Of Telomeres 1 (Pot1) proteins form foci at the telomeres of germ cells that disappear at fertilization and gradually accumulate during development. We find that gametes from mutants deficient for Pot1 proteins alter levels of telomeric foci for multiple generations. Gametes from pot-2 mutants give rise to progeny with abundant POT-1::mCherry and mNeonGreen::POT-2 foci throughout development, which persists for six generations. In contrast, gametes from pot-1 mutants or pot-1; pot-2 double mutants induce diminished Pot1 foci for several generations. Deficiency for MET-2, SET-25, or SET-32 methyltransferases, which promote heterochromatin formation, results in gametes that induce diminished Pot1 foci for several generations. We propose that C. elegans POT-1 may interact with H3K9 methyltransferases during pot-2 mutant gametogenesis to induce a persistent form of transgenerational epigenetic inheritance that causes constitutively high levels of heterochromatic Pot1 foci.


Assuntos
Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/deficiência , Gametogênese , Células Germinativas/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Telômero/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/genética , Epigênese Genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Hereditariedade , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Masculino , Telômero/genética , Proteínas de Ligação a Telômeros/genética
16.
PLoS One ; 16(2): e0246750, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33630916

RESUMO

Genetic selection in parental broiler breeders has increased their susceptibility to metabolic disorders and reproductive dysfunction. We have recently shown that maternal dietary grape seed extract (GSE) supplementation in hens improves fertility parameters, egg quality, oxidative stress in different tissues and the quality of F1 chicks. Here, we analysed the growth and fertility (both female and male) of the F1 generation animals and the quality of their offspring (F2 generation). Eggs issued from hens supplemented with GSE presented lower ROS production than control hens, suggesting a change in the embryonic environment. However, this did not affect the growth nor the body composition of male and female F1s from hatching to adulthood (37 weeks of age). At 37 weeks of age, the biochemistry analysis of the GSE-F1 muscle has revealed an increase in sensitivity to oxidative stress and a slight change in lipid composition. Both male and female F1-GSE groups presented a delay in puberty with a lower testis volume at 30 weeks of age and lower ovary development at 26 weeks of age. Adult GSE-F1 males did not present histological alterations of seminiferous tubules or semen production, but the semen quality was degraded due to higher oxidative stress and DNA-damaged spermatozoa compared with control F1 animals. In adult GSE-F1 females, despite the delay in puberty, the females laid more eggs of better quality (fewer broken eggs and a higher hatching rate). At hatching, the weight of the chicks from GSE-F1 females was reduced, and this effect was stronger in F2 male chicks (F2) compared with F2 control chicks (F2), because of the lower muscle volume. In conclusion, we can raise the hypothesis that maternal dietary GSE supplementation produces eggs with change in embryonic metabolism, which may affect in adulthood the fertility. The data obtained from the F1-GSE group pointed to a sex-specific modification with higher egg quality in females but semen sensitive to stress in males. Finally, male F2 chicks were leaner than control chicks. Thus, maternal dietary grape seed extract (GSE) supplementation in hens may impact on the fertility of the offspring in a sex-specific manner in subsequent generations.


Assuntos
Cruzamento/métodos , Galinhas/crescimento & desenvolvimento , Fertilidade/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Hereditariedade/efeitos dos fármacos , Sêmen/efeitos dos fármacos , Animais , Suplementos Nutricionais , Ovos/normas , Feminino , Fertilidade/fisiologia , Masculino , Desenvolvimento Muscular/efeitos dos fármacos , Ovário/citologia , Ovário/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Reprodução , Sêmen/metabolismo , Análise do Sêmen , Maturidade Sexual , Testículo/citologia , Testículo/efeitos dos fármacos , Tomografia Computadorizada por Raios X
17.
Commun Biol ; 4(1): 207, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594200

RESUMO

Environmental conditions can cause phenotypic changes, part of which can be inherited by subsequent generations via soma-to-germline communication. However, the signaling molecules or pathways that mediate intertissue communication remain unclear. Here, we show that intertissue small RNA communication systems play a key role in the acquisition and inheritance of hormesis effects - stress-induced stress resistance - in Caenorhabditis elegans. The miRNA-processing enzyme DRSH-1 is involved in both the acquisition and the inheritance of hormesis, whereas worm-specific Argonaute (WAGO) proteins, which function with endo-siRNAs, are involved only in its inheritance. Further analyses demonstrate that the miRNA production system in the neuron and the small RNA transport machinery in the intestine are both essential for its acquisition and that both the transport of small RNAs in the germline and the germline Argonaute HRDE-1 complex are required for its inheritance. Our results thus demonstrate that overlapping and distinct roles of small RNA systems in the acquisition and inheritance of hormesis effects.


Assuntos
Proteínas Argonauta/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimologia , Hormese/genética , MicroRNAs/metabolismo , Transporte de RNA , RNA Interferente Pequeno/metabolismo , Ribonuclease III/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas Argonauta/genética , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Hereditariedade , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Intestinos , MicroRNAs/genética , Neurônios/metabolismo , Pressão Osmótica , Estresse Oxidativo , Interferência de RNA , RNA Interferente Pequeno/genética , Ribonuclease III/genética
18.
Hist Philos Life Sci ; 43(1): 20, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33569656

RESUMO

Our paper aims at bringing to the fore the crucial role that habits play in Charles Darwin's theory of evolution by means of natural selection. We have organized the paper in two steps: first, we analyse value and functions of the concept of habit in Darwin's early works, notably in his Notebooks, and compare these views to his mature understanding of the concept in the Origin of Species and later works; second, we discuss Darwin's ideas on habits in the light of today's theories of epigenetic inheritance, which describe the way in which the functioning and expression of genes is modified by the environment, and how these modifications are transmitted over generations. We argue that Darwin's lasting and multifaceted interest in the notion of habit, throughout his intellectual life, is both conceptually and methodologically relevant. From a conceptual point of view, intriguing similarities can be found between Darwin's (early) conception of habit and contemporary views on epigenetic inheritance. From a methodological point of view, we suggest that Darwin's plastic approach to habits, from his early writings up to the mature works, can provide today's evolutionary scientists with a viable methodological model to address the challenging task of extending and expanding evolutionary theory, with particular reference to the integration of epigenetic mechanisms into existing models of evolutionary change. Over his entire life Darwin has modified and reassessed his views on habits as many times as required by evidence: his work on this notion may represent the paradigm of a habit of good scientific research methodology.


Assuntos
Evolução Biológica , Epigênese Genética , Epigenômica/história , Hábitos , Hereditariedade , Seleção Genética , História do Século XIX
19.
Zhonghua Gan Zang Bing Za Zhi ; 29(1): 5-8, 2021 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-33541016

RESUMO

With the economic development and living standards improvement, various chronic viral liver diseases in children is decreasing year by year, and the liver diseases related to heredity, environment and living habits is increasing. Although liver disease in children is relatively rare and is not the main cause of childhood mortality, chronic liver disease cannot be ignored for its effect on children's growth and development, mental health, quality of life and the economic burden to family or society. Therefore, more attention should be paid to the early screening, diagnosis and treatment of pediatric liver diseases, in order to delay or prevent its progression efficiently.


Assuntos
Hereditariedade , Hepatopatias , Criança , Progressão da Doença , Humanos , Hepatopatias/diagnóstico , Hepatopatias/epidemiologia , Qualidade de Vida
20.
Am J Med Genet B Neuropsychiatr Genet ; 186(2): 90-100, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33484094

RESUMO

Philipp Jolly's 1913 extensive monograph "The Heredity of Psychoses" provides, in both his detailed literature review and new pedigree study, an extensive assessment of a key issue in the psychiatric genetics of his day: the degree to which the familial transmission of psychiatric disorders was specific (or homogeneous) versus nonspecific (or heterogeneous). Contrary to a number of earlier observations, Jolly concludes that heterogeneous transmission is rare. Multiple psychiatric disorders can occur in one family because members of a family may have elevated predispositions to more than one disorder rather than one predisposition which increases risk for a wide range of conditions. A notable exception to this, he notes, is within manic-depressive illness (MDI), where different forms of illness run together within families. Jolly is also among the earliest investigators to evaluate simple Mendelian models for MDI and dementia praecox (DP). While his methods were primitive and contained only "eye-ball" examinations rather than statistical modeling, Jolly demonstrated considerable conceptual sophistication in the early application of such models. He concludes that DP is likely a recessive disorder. MDI, he states, is either a recessive condition or demonstrates "gender-based dominant heredity" where heterozygote females are affected, and heterozygote males are not.


Assuntos
Transtorno Bipolar/genética , Demência/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença , Hereditariedade , Transtornos Psicóticos/genética , Transtorno Bipolar/patologia , Demência/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Análise da Randomização Mendeliana , Transtornos Psicóticos/patologia
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